“PHF19 on its own already tells us something about how patients will fare, but combining it with five other genes is a dramatic improvement which gives us more accurate information for AML prognosis,” says ICREA Research Professor Luciano Di Croce, senior author of the study and researcher at the CRG. The researchers say the score could contribute to the development of future prognostic tests. Patients suspected of having AML already provide a bone marrow sample for laboratory analysis, and measuring six genes would be simpler and cheaper than reading a broader genetic profile. Some of the genes have never previously been linked to blood cancer. “These genes haven’t been described in leukaemia or even in how blood forms. We don’t yet know what they are doing there, which is exactly what makes them worth exploring,” says Dr. Gianni Gamarra, first author of the study.

The findings grew out of an initial focus on PHF19 alone. The gene belongs to a family of genes that keep other genes switched off, a system cells use as they progress along the differentiation process from immature to mature cells, and it is generally thought to suppress blood cancer formation. Earlier work in Di Croce’s laboratory, which has studied PHF19 for more than a decade, showed that mice lacking the gene develop a condition resembling myelodysplastic syndrome, in which blood cells fail to mature properly and build up in the body without yet becoming cancerous. “Leukaemia develops in stages, as a cell gradually accumulates defects,” explains Gamarra. “Losing PHF19 doesn’t cause leukaemia on its own, but it is already a push down that road.”

The new study asked what happens when leukaemia originates in cells that start from similar intermediate conditions, not cancerous but not fully healthy either. The researchers introduced a leukaemia-causing gene into mouse blood cells with and without PHF19. Cells lacking the gene formed more colonies in the laboratory and, when transplanted into mice, took hold more easily. They also remained locked in an immature, stem-cell-like state. “Blood cells form a hierarchy,” says Gamarra. “At the top are stem cells, which are still plastic and could become almost anything. As they move down, they mature and take on a fixed identity. The more a cancer holds on to that plasticity, the more malignant it tends to be.”

That plasticity also made the cells harder to treat. In the mouse experiments, cells without PHF19 largely ignored the effects of chemotherapeutic drugs that are commonly used to push leukaemia cells into a mature state, one of the strategies doctors use against a disease in which cells become stuck partway through development and multiply unchecked. These are observations in mouse models and laboratory-grown cells, not demonstrated clinical benefits in patients.

To check whether the mouse model reflected human disease, the researchers compared which genes were switched on and off in the mouse cells and in data generated from human studies. The same pattern appeared in patient datasets. Among younger adults treated for AML, those with the lowest levels of PHF19 survived for less time than those with the highest levels. They were also less likely to go into remission after standard chemotherapy: fewer than half did so, compared with up to 85 percent of patients with the highest PHF19 levels. These figures are associations observed in the studied patient groups rather than predictions for any individual patient, and the six-gene score has not yet been validated as a clinical test.

“The patients have advanced leukaemia, so we are comparing mice and humans at very different stages of the disease, yet the molecular data point in the same direction, which gives our model a great deal of strength,” says Gamarra Figueroa. The convergence between the mouse model and human datasets is the study’s central methodological strength, but the stage mismatch between the two remains a limitation the authors themselves acknowledge.

The study took five years to complete. It was led by Luciano Di Croce and Gianni Gamarra at the CRG, with single-cell expertise from Lars Velten’s group and support from the CRG’s Genomics Unit and Flow Cytometry Unit. The work lays foundations for new ways of predicting how AML patients will fare with a blood cancer whose outcomes vary widely from one patient to the next, and it identifies genes that could also be explored as potential therapeutic targets, though any such applications remain speculative until the mechanisms of these newly implicated genes are understood.

Subject of Research: A six-gene prognostic score for acute myeloid leukaemia survival based on mouse models and patient data

Article Title: Six-gene scoring system could help predict leukemia survival

Article References: Six-gene scoring system could help predict leukemia survival. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: acute myeloid leukaemia, PHF19, PHFScore, gene expression, prognosis, Polycomb, Centre for Genomic Regulation, mouse models, blood cancer, differentiation, chemotherapy resistance, Science Advances

The evidence supports a model in which a molecule’s biological effect depends not only on its target genes, but also on where it is located, which cell receives it and how it is delivered. The review describes microRNAs, or miRNAs, as short, typically 18–22-nucleotide RNA molecules that regulate gene expression after transcription. They are transcribed as primary miRNAs and processed in the nucleus by the Drosha–DGCR8 Microprocessor complex, exported to the cytoplasm by exportin-5 and cleaved by Dicer into miRNA duplexes.

One strand is preferentially loaded into an Argonaute protein to form the RNA-induced silencing complex, which recognizes complementary response elements in target messenger RNAs and usually promotes their degradation or inhibits their translation. Canonical binding sites occur mainly in the 3-prime untranslated regions, although functional sites can also appear in the 5-prime untranslated region and coding sequences. Mature miRNAs and Argonaute-containing complexes can also enter the nucleus, where they may influence transcription-factor recruitment, DNA methylation, histone modifications and chromatin accessibility.

This regulatory system therefore has effects beyond the conventional cytoplasmic pathway. Within cancer cells, miR-142-3p is frequently reduced, and the available studies place this loss alongside more advanced disease or poorer treatment response. In lung adenocarcinoma, the review reports that expression was lower in approximately 52% of tumors than in adjacent normal tissue, while low levels were associated with larger tumors, advanced stage, lymph-node metastasis and treatment resistance.

Reduced expression has also been documented in breast, colorectal, gastric and ovarian cancer tissue or cell lines. Its effects are not universal, however, and the supporting experiments come from heterogeneous cancer models, including cultured cells and selected animal studies rather than a single large clinical cohort. The expression patterns also do not, on their own, establish the extent to which miR-142-3p loss causes tumor progression in patients.

One of the best-supported intracellular targets is high mobility group box 1, or HMGB1. In cervical cancer models, miR-142-3p bound the 3-prime untranslated region of HMGB1 messenger RNA, reduced HMGB1 expression and increased markers of apoptosis, including cleaved PARP, caspase-3, caspase-7, caspase-9 and BAX, while lowering anti-apoptotic Bcl-2 and Bcl-xL. Related suppressive effects were observed in glioma, where the RNA reduced cell viability and induced apoptosis through HMGB1 inhibition.

Other mechanisms include targeting CIAPIN1 in leukemia, Rac1/ERK signaling in colorectal cancer and FZD7 in cervical cancer, where FZD7 suppression inhibited oncogenic Wnt/beta-catenin signaling. These findings show that miR-142-3p can act through several context-dependent targets, but they do not establish that any single mechanism accounts for its behavior in human cancers. The molecule also appears to restrain epithelial–mesenchymal transition, a process in which cancer cells lose epithelial features and acquire properties associated with motility, invasion and dissemination.

In cervical cancer, increased miR-142-3p raised E-cadherin while reducing vimentin, N-cadherin, Snail and ZEB1, with corresponding reductions in migration and invasion. Suppression of FZD7 was linked to reduced beta-catenin nuclear translocation, while reduced NF-kappaB activity may also have contributed. Breast cancer experiments implicated CXCL12 and BACH1, and colorectal cancer experiments implicated Rac1/PERK signaling.

In lung cancer, miR-142-3p directly targeted NR2F6 and reduced MMP2 and MMP9; an MMP inhibitor abolished the migration induced by miR-142-3p knockdown. Most of these observations were generated in cell cultures, with some supporting animal experiments, so their clinical relevance remains incompletely defined. Chemosensitivity provides another major strand of evidence.

The review reports that miR-142-3p can enhance responses to agents including cisplatin, doxorubicin, docetaxel and paclitaxel in breast, lung and ovarian cancer models. In non-small-cell lung cancer, it targeted HMGB1, altered mTOR signaling and suppressed protective autophagy, increasing the effects of cisplatin and doxorubicin; tumors engineered to overexpress the RNA also responded more strongly to chemotherapy in vivo. In ovarian cancer, targeting SIRT1 sensitized resistant SKOV3 cells to cisplatin, and in H1299 lung cancer cells, SIRT1 suppression reduced autophagy and increased cisplatin sensitivity, with restoration of SIRT1 reversing the effect.

Other experiments linked miR-142-3p to apoptosis, stemness-associated proteins and reduced drug efflux. These are preclinical observations and do not establish that adding miR-142-3p would improve outcomes in treated patients. The review also notes that low intracellular miR-142-3p and higher levels in vesicles from chemoresistant cells have been observed relative to chemosensitive counterparts, but this does not prove that vesicle export causes resistance.

Extracellular vesicles are membrane-bound particles that transport proteins, lipids and nucleic acids between cells. Cancer cells can release more vesicles than nonmalignant cells, and therapeutic stress or drug resistance may increase release further. Limited evidence indicates that miR-142-3p is selectively enriched in tumor-derived vesicles: early lung adenocarcinoma cells produced vesicles containing more than four times the amount found in donor cells, and RNA-sequencing data from cervical cancer lines likewise showed higher extracellular than intracellular levels.

RNA-binding protein SYNCRIP recognizes a GGCU motif found in miR-142-3p and has been linked to sorting miRNAs into vesicles, offering a possible mechanism for this enrichment. Export could therefore lower a tumor cell’s internal tumor-suppressive activity while delivering a potentially supportive signal to recipients. The proposed link between export and intracellular depletion remains a mechanistic interpretation, because the review reports enrichment in selected models rather than a time-resolved demonstration in patients.

Recipient-cell evidence remains limited but is clearest for fibroblasts and blood vessels. In a lung adenocarcinoma model, vesicles transferred miR-142-3p to fibroblasts and increased canonical cancer-associated fibroblast markers, alpha-smooth muscle actin and PDGFR-beta, as well as migratory activity. Neither vesicle treatment nor direct overexpression significantly changed TGF-beta signaling, leaving the mechanism unresolved, and the result has not yet been demonstrated across tumor types or established in vivo.

For angiogenesis, miR-142-3p-enriched vesicles from oral cancer enhanced endothelial-cell angiogenesis in laboratory and animal experiments, while vesicles from regulatory T cells promoted proliferation, migration, cell-cycle progression and tube formation in human umbilical vein endothelial cells. Both settings implicated direct targeting of TGFBR1 and reduced TGF-beta/Smad signaling, potentially reducing anti-angiogenic mediators such as thrombospondin-1 and soluble Fms-like tyrosine kinase-1. A separate choroidal-neovascularization model showed that inhibiting miR-142-3p reduced vascular growth, but its relevance to cancer-associated angiogenesis was not tested.

Immune effects vary with cellular context and are not uniformly tumor-promoting. Overexpression in macrophages and dendritic cells was associated with reduced antigen processing, impaired antigen uptake and clearance, increased PD-L1 expression and lower production of the Th1-associated cytokines TNF-alpha and IFN-gamma; PD-L1 blockade restored T-cell proliferation in that experimental system. That study did not examine extracellular-vesicle delivery or cancer-specific immunity.

Conversely, vesicles from M1 macrophages carried miR-142-3p into glioblastoma cells, where the RNA suppressed HMGB1 and STAT3 signaling and reduced PD-L1, alleviating tumor-cell immune suppression. A separate hepatocellular carcinoma model linked intracellular miR-142-3p to suppression of ASH1L and increased immune activity, but did not test vesicle transfer. These studies used different sources, recipients and delivery mechanisms, leaving unresolved which variables determine whether the RNA strengthens or weakens antitumor immunity.

The most direct evidence for tumor-derived vesicles transferring the RNA into M1 macrophages came from hepatitis B virus-associated hepatocellular carcinoma, where the reported outcome was ferroptosis and tumor promotion; this is a specific experimental context rather than a general immune mechanism. The review also identifies cachexia as a hypothesis rather than a demonstrated cancer mechanism. Cancer-associated cachexia, characterized by weight loss and progressive skeletal muscle loss, affects an estimated 50–80% of patients with advanced disease and is associated with poorer survival and reduced treatment tolerance.

Direct evidence that tumor-derived vesicle miR-142-3p causes cachexia is absent. However, non-cancer experiments showed that miR-142-3p targets MEF2A in C2C12 myoblasts, disrupting cell-cycle progression and myotube formation; reducing miR-142-3p after nerve injury preserved muscle mass, strength, myofiber diameter and satellite-cell activity in mice. These findings make myogenic disruption a possible route to investigate, but they do not establish a role in cancer-associated cachexia.

Therapeutic development faces the central challenge that restoring miR-142-3p in tumor cells could restore growth suppression yet unintentionally support fibroblasts or endothelial cells if delivery is not precisely controlled. Mimics, chemically stabilized carriers, engineered vesicles and selective interruption of vesicle release or uptake are being investigated, but most programs remain preclinical, and available approaches may also affect physiologically important extracellular communication.

Subject of Research: Context-dependent tumor-suppressive and extracellular signaling functions of miR-142-3p

Article Title: miR-142-3p in cancer: intracellular tumor suppression and extracellular vesicle- mediated microenvironmental signaling

Article References: van der Merwe, M., Towle, R., Myburgh, K., Garnis, C., & Engelbrecht, A.-M. (2026). miR-142-3p in cancer: intracellular tumor suppression and extracellular vesicle- mediated microenvironmental signaling. Molecular Biology Reports, 53(1), Article 1501. https://doi.org/10.1007/s11033-026-12631-y

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12631-y

Keywords: miR-142-3p, cancer biology, extracellular vesicles, tumor microenvironment, chemotherapy resistance, angiogenesis, cancer-associated fibroblasts, immune modulation, cachexia, microRNA therapeutics, cancer, intracellular

The investigation combined two partially overlapping analytical cohorts drawn from the same surgical population. Cohort A included 430 patients with complete information for the clinical variables considered in a prediction model for PNI. The researchers used least absolute shrinkage and selection operator regression, multivariable logistic modeling and bootstrap corrections to develop a six-factor nomogram based on pathological T stage, N stage, lymphovascular invasion, tumor budding, KRAS mutation status and Ki-67 expression. Cohort B consisted of 390 patients with valid ATP-based tumor chemosensitivity records. Its complete-covariate subset included 292 patients and was used to test the relationship between PNI and capecitabine sensitivity through ordinal regression, inverse probability of treatment weighting and propensity-score matching. The two analytical cohorts partially overlapped, but model development and chemosensitivity testing were conducted separately to limit information leakage.

All participants had histologically confirmed colorectal adenocarcinoma and underwent R0 resection between January 2024 and August 2025. The researchers excluded patients with another primary malignancy, those who received neoadjuvant chemoradiotherapy before surgery, and those with hereditary colorectal cancer syndromes. Follow-up ranged from eight to 27 months, with a median of 18 months, and ended with a database lock on March 31, 2026. PNI was defined using the Liebig criteria: tumor cells had to encircle at least 33% of a nerve’s circumference or involve a layer of the nerve sheath. Two senior gastrointestinal pathologists independently reviewed hematoxylin-and-eosin-stained slides while blinded to clinical outcomes.

Among all 724 patients, 630 tumors were PNI-negative and 94 were PNI-positive. The PNI-positive group more frequently had pT3 disease, lymphovascular invasion, lymph-node metastasis and the highest category of tumor budding. KRAS mutations were also more common in PNI-positive tumors. In contrast, high Ki-67 expression was less prevalent in that group, at 89% compared with 96%, despite the tumors’ greater overall aggressiveness. Patients with and without PNI did not differ significantly by age, sex or tumor location. The investigators interpreted the lower Ki-67 prevalence cautiously, suggesting that PNI may reflect a more migratory, microenvironment-dependent invasion pattern rather than simply more rapid proliferation. They emphasized that Ki-67 functions in the model as an adjustment variable and that this proposed interpretation requires mechanistic confirmation.

The six-factor nomogram produced an area under the receiver operating characteristic curve of 0.778 in its development subset, 0.741 in an internal hold-out group of 129 patients and 0.803 across the full 430-patient Cohort A. The difference between development and hold-out AUCs was 0.037, below the researchers’ prespecified threshold of 0.05 for acceptable generalizability. Calibration appeared satisfactory: the mean absolute error was 0.023, and a Hosmer–Lemeshow test for the hold-out subset did not indicate a significant lack of fit. Decision-curve analysis suggested positive net benefit at threshold probabilities of roughly 5% to 40%. These are internal performance results, however, rather than evidence from an external multicenter cohort. The model also relied on complete-case data, and 294 of the original patients lacked one or more candidate variables. The authors said the model could complement rather than replace direct pathological assessment, particularly where sampling is limited or interpretation varies among observers.

Distant metastasis was documented in 84 patients during the available follow-up. Because exact metastasis and censoring dates could not be reconstructed consistently from routine records, the investigators did not perform a primary time-to-event analysis. Instead, they used binary logistic regression to estimate associations. PNI was associated with distant metastasis in the unadjusted analysis, with an odds ratio of 2.80 and a 95% confidence interval of 1.60 to 4.77. In a model containing PNI, lymphovascular invasion and N stage, the adjusted odds ratio remained 2.38, with a 95% confidence interval of 1.32 to 4.17 and P = 0.003. Firth penalized logistic regression produced a nearly identical result, with an odds ratio of 2.38, a 95% confidence interval of 1.33 to 4.14 and P = 0.004. The baseline risk of distant metastasis among PNI-negative patients was 9.84%, or 62 of 630 patients. A sensitivity analysis restricted to at least 12 months of follow-up retained the same direction of association.

Subgroup analyses generally followed the same direction, including strata defined by age, sex, tumor location, T3 and N2 stage, lymphovascular invasion and KRAS wild-type status. The association was not significant in the T2, N0, N1 or KRAS-mutant subgroups, which the authors treated as exploratory rather than evidence of a definitive interaction. An apparent stronger association in KRAS wild-type tumors, with an odds ratio of 4.61 and a 95% confidence interval of 1.99 to 10.24, was not supported by a statistically significant PNI-by-KRAS interaction test, for which P = 0.107. The researchers also calculated an E-value of 3.61, with a lower confidence limit of 1.88. Under the study’s assumptions, an unmeasured confounder would need to be associated with both PNI and distant metastasis by a risk ratio of at least 3.61 to explain away the observed adjusted association. This estimate addresses the potential influence of unmeasured variables but cannot rule it out.

Capecitabine sensitivity was evaluated in patient-derived tumor cells exposed for 72 hours to six concentrations ranging from 6.25% to 200% of the theoretical drug concentration, defined from the peak plasma concentration expected with standard-dose capecitabine. Cellular ATP served as the measure of viability, and responses were classified into four grades based on inhibitory concentrations and a composite index. In PNI-negative tumors, 12.6% were classified as highly sensitive and 9.1% as resistant. Among PNI-positive tumors, the resistant proportion rose to 22.4%, while the highly sensitive proportion fell to 10.2%. In the unweighted cohort, PNI positivity was associated with reduced sensitivity, with an odds ratio of 0.50 and a 95% confidence interval of 0.27 to 0.91. The direction persisted after multivariable adjustment, but that initial estimate did not reach statistical significance: its 95% confidence interval was 0.25 to 1.09 and P = 0.085.

Stronger results emerged after the researchers controlled for measured confounding through weighting and matching, although the effective sample size for PNI-positive cases was smaller. After inverse probability of treatment weighting, PNI was associated with reduced capecitabine sensitivity in the univariate model, with an odds ratio of 0.60 and a 95% confidence interval of 0.43 to 0.83, and in the multivariable model, with an odds ratio of 0.62, a 95% confidence interval of 0.44 to 0.88 and P = 0.007. Propensity-score matching produced 90 pairs and a multivariable odds ratio of 0.34, with a 95% confidence interval of 0.15 to 0.77 and P = 0.009. Ordinal and multinomial sensitivity analyses pointed in the same direction, and formal tests did not detect a violation of the proportional-odds assumption. These remain observational associations, however: weighting and matching can address differences in measured covariates, but residual confounding from unmeasured factors remains possible, and the cell assay does not reproduce drug metabolism, immune surveillance or other features of treatment in a patient.

The assay also requires particular caution because capecitabine is a prodrug and no exogenous activation system was added. The authors noted that colorectal cancer cells can express enzymes such as thymidine phosphorylase and generate the active metabolite 5-fluorouracil locally, but incomplete activation within the culture system cannot be excluded. The study did not establish that PNI modifies the effectiveness of capecitabine in patients. Only five deaths occurred during the available follow-up, precluding robust analyses of disease-free or overall survival. The single-center retrospective design, missing-data restrictions, limited follow-up and lack of external validation further constrain generalization. Prospective studies with clinical treatment outcomes, active-metabolite testing and longer follow-up would be needed before the findings could justify changes to fluoropyrimidine-based treatment. For now, the results offer a hypothesis for future work and a possible approach to postoperative risk stratification, not a clinical directive.

Subject of Research: Associations of perineural invasion with distant metastasis and in vitro capecitabine sensitivity in resected colorectal adenocarcinoma

Article Title: Perineural invasion is associated with an aggressive phenotype and reduced in vitro capecitabine sensitivity in colorectal cancer

Article References: Yang, S., Bai, Z., Li, Y., Mao, C., Han, T., Liang, S., & Xi, Y. (2026). Perineural invasion is associated with an aggressive phenotype and reduced in vitro capecitabine sensitivity in colorectal cancer. Frontiers in Oncology, 16, Article 1961159. https://doi.org/10.3389/fonc.2026.1961159

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1961159

Keywords: colorectal cancer, perineural invasion, capecitabine sensitivity, distant metastasis, patient-derived tumor cells, chemotherapy resistance, pathology, risk prediction, KRAS, tumor microenvironment, Perineural, invasion

Primary pulmonary choriocarcinoma is an exceptionally rare, non-gestational trophoblastic malignancy that occurs predominantly in the lung and is especially uncommon in men. The tumor is characterized by rapid growth, extensive hemorrhage and necrosis, early hematogenous spread and frequently poor response to chemotherapy. Its symptoms are nonspecific, commonly including cough, hemoptysis, chest pain and breathlessness, which can lead to an initial diagnosis of conventional lung cancer. There is currently no established standard treatment, and the optimal management and prognostic factors for the disease remain poorly characterized.

The patient in the case report had experienced intermittent cough for six months when he presented to Linyi Central Hospital in Shandong, China. Chest computed tomography showed a heterogeneous right upper-lobe mass measuring approximately 10.2 by 8.6 centimeters, together with multiple nodules in the opposite lung that were interpreted as intrapulmonary metastases. Brain magnetic resonance imaging demonstrated multiple lesions with surrounding edema, including a 3.6 by 3.3-centimeter mass in the right cerebellar hemisphere. Routine blood tests were otherwise largely unremarkable, but his serum β-HCG concentration exceeded 10,000 mIU/mL.

A CT-guided biopsy of the lung mass showed extensive hemorrhage and necrosis with a biphasic population of malignant cells: mononuclear cytotrophoblasts mixed with multinucleated syncytiotrophoblasts. The cells stained diffusely for β-HCG, cytokeratin 7, GATA3 and SALL4, while TTF-1, Napsin A, CK5/6 and Glypican-3 were negative. The Ki-67 labeling index was approximately 70%. Focal p40 positivity created a potential diagnostic trap because it could support a diagnosis of poorly differentiated squamous-cell carcinoma, but the combined morphology, immunophenotype and serum β-HCG findings favored pulmonary choriocarcinoma.

The investigators acknowledged an important limitation in establishing the tumor’s primary site. The large lung mass and absence of a palpable testicular abnormality supported a diagnosis of primary pulmonary choriocarcinoma, but scrotal ultrasonography and postmortem examination were not performed. An occult or regressed testicular primary therefore could not be completely excluded. Genomic profiling and testing for PD-L1 expression, tumor mutational burden and microsatellite instability were also unavailable because of financial constraints, leaving potential predictors of immune-checkpoint response unassessed. The investigators therefore described the diagnosis as the one most consistent with the available clinical and pathological evidence.

Treatment began with radiotherapy to the brain metastases on June 16, 2025, but it was stopped because of poor tolerance. The patient then received three cycles of EMA/CO chemotherapy. β-HCG initially declined but subsequently rose again, and imaging showed new metastases in the left cerebellar hemisphere, right frontal lobe and left thalamus. On August 31, the regimen was changed to EMA/EP, with the PD-1 inhibitor sintilimab administered during the first cycle and subsequent cycles continuing without it. The biomarker fell temporarily, but persistent pulmonary lesions and progressive intracranial disease showed that the response was not sustained. Further brain radiotherapy and later thoracic radiotherapy likewise failed to arrest progression.

A third-line combination of nab-paclitaxel, bevacizumab and the PD-1 inhibitor penpulimab was started on January 9, 2026, with additional cycles on January 31 and February 25. β-HCG again decreased temporarily, but the patient ultimately developed rapid pulmonary and intracranial progression. After discussion with his family, active anticancer treatment was stopped and best supportive and palliative care was provided. He was discharged on March 4, 2026, about 8.6 months after pathological diagnosis, still alive but in poor condition because of persistent intracranial and systemic disease. No objective laboratory or imaging follow-up was available after discharge.

One of the report’s most notable observations was the close relationship between serial β-HCG measurements and radiological changes. Temporary reductions in β-HCG accompanied periods of apparent treatment response, while renewed increases corresponded with disease progression. The authors report that changes in the marker sometimes preceded or occurred alongside changes visible on imaging, allowing clinicians to recognize resistance earlier. This case does not establish that β-HCG can replace imaging, but it shows how a relatively simple blood test tracked the course of a tumor that produced exceptionally high hormone concentrations in this patient.

The investigators searched PubMed for eligible English-language reports of confirmed male primary pulmonary choriocarcinoma, extracting clinical presentation, metastatic sites, pretreatment β-HCG, treatment and survival data. Their analyses included 33 metastatic cases with available survival information and a separate set of 18 cases with pretreatment β-HCG values suitable for prognostic analysis. In exploratory Kaplan–Meier analyses, patients receiving immune checkpoint inhibitor-based therapy had significantly longer overall survival than those treated without immunotherapy, and patients with lower pretreatment β-HCG also had longer survival than those with markedly elevated concentrations. These were associations in small, heterogeneous, published case cohorts, not randomized comparisons; differences in disease severity, treatment selection, follow-up and publication bias could influence the results.

Taken together, the case illustrates the diagnostic and therapeutic difficulty of male primary pulmonary choriocarcinoma while providing preliminary support for two areas of further study. Pathology must integrate morphology and multiple immunohistochemical markers with serum β-HCG rather than depend on any single stain, and treatment decisions in advanced disease remain unsupported by standardized guidelines or prospective trials. Dynamic β-HCG measurement may be useful for monitoring tumor burden in individual patients, while the pooled survival signal warrants investigation of checkpoint blockade in larger, multicenter cohorts. The authors emphasized that prospective studies incorporating genomic and immune biomarkers are needed to determine whether immunotherapy improves outcomes in this exceptionally rare and aggressive cancer.

Subject of Research: Clinical features, monitoring and treatment of male primary pulmonary choriocarcinoma with brain metastases

Article Title: Primary pulmonary choriocarcinoma with brain metastases in a male: a case report and literature review

Article References: Yin, Z., Xiao, Y., Zhang, D., Liu, B., & Liu, S. (2026). Primary pulmonary choriocarcinoma with brain metastases in a male: a case report and literature review. Frontiers in Oncology, 16, Article 1945521. https://doi.org/10.3389/fonc.2026.1945521

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1945521

Keywords: primary pulmonary choriocarcinoma, brain metastases, β-human chorionic gonadotropin, immune checkpoint inhibitors, trophoblastic malignancy, case report, survival analysis, tumor monitoring, immunohistochemistry, Primary, pulmonary, choriocarcinoma

RRM2 is not an unfamiliar name in oncology. As the regulatory subunit of ribonucleotide reductase, the enzyme complex that converts ribonucleotides into the deoxyribonucleotides needed for DNA synthesis and repair, it is essential for proliferating cells and has previously been associated with aggressive disease in several tumor types. What makes the new work distinctive is its attempt to connect RRM2 to lipid biology and to chemotherapy response within the same framework, using a combination of bulk transcriptomic data, clinical survival information, single-cell RNA sequencing, tissue-level protein evidence, and a battery of laboratory experiments in pancreatic cancer cell lines and mouse models.

The bioinformatic arm of the study established the clinical backdrop. RRM2 was found to be upregulated in pancreatic ductal adenocarcinoma compared with non-tumor tissue, and elevated expression tracked with unfavorable clinical characteristics and shorter overall survival. When the researchers examined the molecular programs that RRM2 expression correlated with, they found a signature that went well beyond simple proliferation. RRM2 levels were associated with hypoxia, epithelial-mesenchymal transition, and, notably, fatty-acid-metabolism-related programs, with correlations to genes such as FASN, the enzyme that manufactures fatty acids from scratch; ACSL4, which activates fatty acids for further metabolism; PLIN2, a marker of lipid droplets; SCD, which desaturates fatty acids; and SREBF1, the master transcription factor controlling the lipogenic program.

That correlation set the stage for the study’s central experiment. The team exposed PANC-1 and SW1990 pancreatic cancer cells to palmitate, a saturated fatty acid, to mimic the lipid-rich conditions that pancreatic tumors often encounter, and then tested how the cells responded to gemcitabine. The result was striking: palmitate exposure increased the IC50 value of gemcitabine, meaning that substantially more drug was required to achieve the same killing effect. Under these lipid-stressed conditions, the cells adopted a recognizable phenotype characterized by high RRM2, high thymidylate synthase (TYMS), low DCK, the enzyme that activates gemcitabine inside the cell, high FASN, high ACSL4, and elevated PCNA, a proliferation marker. Lipid-droplet accumulation, visualized with BODIPY 493/503 staining, accompanied this shift.

To test whether RRM2 was merely a passenger or an active participant in this drug-tolerant state, the researchers depleted it using small interfering RNA. The consequences were broad. RRM2 knockdown reduced the gemcitabine IC50, meaning the cells became more sensitive to the drug. It also suppressed lipid accumulation and proliferative markers, and, importantly, restored expression of DCK, the very enzyme that pancreatic tumors often lose to deactivate gemcitabine. At the same time, the treated cells accumulated more γ-H2AX, a molecular beacon for DNA double-strand breaks, and showed increased apoptosis. When the team re-expressed RRM2 in the depleted cells, these effects were partially reversed, supporting a causal role for the gene rather than an off-target artifact of the knockdown procedure.

The study then probed the mechanism linking RRM2 to fat metabolism. Because RRM2 is a nucleotide-metabolism protein, it cannot directly regulate lipid genes in the way a transcription factor would, so the investigators turned to SREBF1, the gene encoding SREBP1, the transcriptional regulator of fatty-acid synthesis. In a series of reciprocal experiments, they showed that re-expressing SREBF1 in RRM2-depleted cells partially restored lipid accumulation, FASN expression, nuclear SREBP1 protein, and tolerance to gemcitabine. In other words, the lipogenic arm of the phenotype could be rescued independently of RRM2 itself, suggesting that RRM2 and the SREBP1/FASN axis functionally cooperate to produce the gemcitabine-tolerant state rather than one simply causing the other in a linear chain.

Supportive evidence came from an in vivo model using mice fed a high-fat diet, designed to reproduce the metabolic context in which many patients with pancreatic cancer live. In these animals, the high-fat diet attenuated the antitumor activity of gemcitabine, echoing the in vitro finding that lipid abundance blunts drug efficacy. Adding RRM2-targeting siRNA to the high-fat diet plus gemcitabine regimen further reduced xenograft growth and lowered expression of FASN, TYMS, and the proliferation marker Ki-67, while increasing tumor necrosis and γ-H2AX accumulation. The authors are careful to characterize this as supportive rather than definitive evidence of therapeutic benefit, an appropriate level of caution for a xenograft experiment that has not yet been replicated in more faithful models or in patients.

The significance of the work lies in how it reframes gemcitabine resistance. Classic explanations have centered on the drug’s own pathway: insufficient uptake, reduced activation by DCK, accelerated catabolism, or elevated RRM2 itself, which allows cells to out-replicate the drug’s damage by maintaining deoxyribonucleotide pools. The new study does not overturn that framework but widens it, proposing that metabolic adaptation, specifically the SREBP1/FASN-driven accumulation of lipid droplets, operates in concert with nucleotide-metabolism changes to create a state in which the tumor is simultaneously better at copying its DNA and better insulated from metabolic stress. A cell in that state is harder to kill with a drug that works by masquerading as a DNA building block.

There are also translational implications, though they come with caveats. If RRM2 depletion genuinely sensitizes tumors to gemcitabine under lipid-rich conditions, then RRM2 inhibitors, some of which have been explored clinically, or dietary and pharmacological interventions that limit lipid availability could theoretically improve chemotherapy response. The study’s own data temper such optimism: the SREBF1 rescue was partial, the in vivo combination experiment was supportive rather than definitive, and the gap between xenografts and human disease in pancreatic cancer is notoriously wide. Single-agent strategies targeting RRM2 have historically struggled with toxicity, because normal proliferating tissues also depend on ribonucleotide reductase.

What the study does provide is a well-integrated map of a phenomenon that clinicians observe daily: patients with pancreatic cancer respond variably to gemcitabine, and metabolic context appears to matter. By tying RRM2 expression to survival, to lipid-metabolism gene programs, and to measurable changes in drug sensitivity, DNA damage, and apoptosis in controlled experiments, the Chongqing-based team has generated a testable hypothesis about how tumor metabolism and chemotherapy resistance interlock. The next steps, validating the RRM2–SREBP1/FASN axis in patient-derived models and determining whether disrupting lipid remodeling can restore gemcitabine efficacy in the clinic, will determine whether this bioinformatic lead matures into a genuine therapeutic strategy for one of medicine’s most stubborn cancers.

Subject of Research: The role of RRM2 in linking lipid metabolic remodeling and gemcitabine resistance in pancreatic ductal adenocarcinoma

Article Title: Integrated bioinformatics identifies RRM2 as a lipid remodeling- and gemcitabine response-related gene in pancreatic cancer

Article References: Song, N., Wu, Y., Wu, Y., Huang, X., & Wang, J. (2026). Integrated bioinformatics identifies RRM2 as a lipid remodeling- and gemcitabine response-related gene in pancreatic cancer. BMC Cancer. https://doi.org/10.1186/s12885-026-16948-6

Image Credits: AI Generated

DOI: 10.1186/s12885-026-16948-6

Keywords: pancreatic cancer, RRM2, gemcitabine resistance, lipid metabolism, SREBF1, FASN, nucleotide metabolism, chemotherapy resistance, bioinformatics, fatty acid synthesis, apoptosis, BMC Cancer

One of the most striking findings comes from Shrestha and colleagues, who investigated two microRNAs, miR-143-3p and miR-506-3p, in non-small cell lung cancer. By combining laboratory cell models with animal studies, they demonstrated that increasing the levels of these two microRNAs significantly reduced cancer cell proliferation and migration while also inhibiting tumor growth in mice. The result points toward a combinatorial microRNA therapy for lung cancer, one of the most common and difficult-to-treat malignancies worldwide.

MicroRNAs are small RNA molecules that regulate gene expression after transcription, essentially acting as molecular brakes on protein production. Because a single microRNA can control dozens of downstream targets simultaneously, they offer a broad-spectrum approach to shutting down multiple cancer-promoting pathways at once. This is particularly relevant in metabolic reprogramming, where cancer cells rely on interconnected networks rather than a single mutated gene.

Building on this concept, Van den Bosch and colleagues developed a synthetic mimic of the tumor-suppressive microRNA miR-7-5p, named 5A2. When formulated in a lipid nanoparticle and delivered as INT-5A2, the treatment produced significant reductions of liver tumors in an experimental mouse model bearing human liver tumors. Remarkably, the researchers found that 5A2 reduced key metabolic enzymes driving glycolysis and glutaminolysis, leading to decreased lactic acid secretion, reduced glycolytic flux and lower intracellular glutamate levels. This suggests that a single microRNA can effectively dismantle the metabolic engine that fuels tumor growth.

Glycolysis and glutaminolysis are two hallmark metabolic pathways exploited by cancer cells. Glycolysis allows tumors to break down glucose even in the presence of oxygen, a phenomenon first described by Otto Warburg nearly a century ago. Glutaminolysis, meanwhile, provides nitrogen and carbon skeletons that support rapid cell division. By simultaneously suppressing both pathways, the 5A2 microRNA mimic essentially starves the tumor of its preferred fuel sources while leaving healthy cells, which depend less heavily on these pathways, relatively unharmed.

Beyond cancer cells themselves, the metabolic environment of the tumor also shapes the immune response. Jin and colleagues reviewed the role of lactic acid, a byproduct of aerobic glycolysis, in regulating tumor-associated macrophages. These immune cells exist along a spectrum from pro-inflammatory M1 macrophages, which attack tumors, to anti-inflammatory M2 macrophages, which support tumor growth and suppress immune responses. Lactic acid has been shown to influence this M1-M2 balance, effectively tipping the tumor microenvironment toward a state that favors cancer progression. The authors argue that targeting lactate metabolism could reprogram these macrophages for enhanced anti-cancer immunity, particularly in solid tumors where immune suppression is strongest.

This metabolic crosstalk between tumor cells and immune cells represents a rapidly growing area of cancer research. Solid tumors create a hostile, nutrient-depleted, lactic acid-rich microenvironment that exhausts cytotoxic T cells and polarizes macrophages toward tumor-supportive states. By intervening in lactate signaling, researchers hope to convert immunologically cold tumors, which respond poorly to immunotherapy, into hot tumors that mount robust anti-cancer immune responses. This could improve the effectiveness of existing checkpoint inhibitors and open new avenues for combination treatments.

Adding another layer of complexity, Zhu and colleagues reviewed the role of mitochondrial ribosomal proteins in cancer. These proteins are essential for translating the thirteen proteins encoded by mitochondrial DNA, and changes in their expression have been linked to significant remodeling of the tumor microenvironment. Specific examples include MRPL13 in breast cancer, MRPL12, MRPL13, MRPL15 and MRPL42 in lung cancer, MRPL43 in colorectal cancer, MRPL9 and MRPL14 in head and neck cancer, and MRPL49 and CRIF1 in acute myeloid leukemia. These alterations drive oxidative stress, reactive oxygen species production, metabolic reprogramming and mitophagy, all of which contribute to cancer cell proliferation and metastasis.

What makes mitochondrial ribosomal proteins particularly exciting is their dual role as both therapeutic targets and prognostic biomarkers. Because their expression patterns differ across cancer types and correlate with disease progression, they could be used to stratify patients during chemotherapy treatment and to assess treatment impact in clinical trials. This aligns with the broader movement toward precision oncology, where molecular profiling of individual tumors guides therapeutic decisions tailored to each patient’s specific cancer biology.

Together, these studies illustrate that cancer’s metabolic rewiring is not a single pathway but an interconnected web spanning microRNA regulation, mitochondrial function, immune cell metabolism and nutrient utilization. While translating these findings into clinically approved treatments will require years of further research, the convergence of microRNA therapeutics, metabolic enzyme inhibitors and immune-modulating agents offers a promising multi-pronged strategy. As researchers continue to decode the metabolic language of tumors, the dream of targeting cancer’s engine room, rather than just its symptoms, moves steadily closer to reality.

Subject of Research: Cancer metabolic reprogramming as a therapeutic target

Article Title: Editorial: Targeting cancer metabolic reprogramming for cancer therapy

Article References: Geldenhuys, W. J., Ji, H. M., & Le, H. V. (2026). Editorial: Targeting cancer metabolic reprogramming for cancer therapy. Frontiers in Drug Discovery, 6, Article 1916506. https://doi.org/10.3389/fddsv.2026.1916506

Image Credits: AI Generated

DOI: 10.3389/fddsv.2026.1916506

Keywords: cancer, metabolism, microRNA, lactate, mitochondria, tumor microenvironment, drug discovery, Editorial, Targeting, metabolic, reprogramming, therapy

Colorectal cancer remains one of the most common malignancies worldwide, and China in particular faces a worsening epidemic marked by rising incidence. Surgery can cure early disease, but advanced patients depend on adjuvant chemotherapy to prevent recurrence. The mainstream FOLFOX and CAPOX regimens extend overall survival to nearly 20 months, with oxaliplatin acting as their platinum backbone. The drug interferes with DNA replication and transcription by forming platinum adducts on DNA. Yet colorectal tumors routinely develop resistance through enhanced DNA repair, heightened autophagy and increased drug efflux, among other mechanisms. This has fueled intense interest in small-molecule sensitizers that can be layered onto existing chemotherapy without adding excessive toxicity.

Ellagic acid has long been an intriguing candidate. It is a polyphenolic dilactone with the formula C14H6O8, bearing two lactone rings and four hydroxyl groups that confer potent antioxidant activity. In plants it exists mainly as ellagitannins, condensed structures that gut microbiota convert into ellagic acid, which is then readily absorbed thanks to its lower molecular weight. Herbal formulas rich in the compound, such as the classic Xihuang Pill, are already used alongside FOLFOX in China to treat colorectal cancer and prevent postoperative recurrence. Earlier laboratory work had shown that ellagic acid can synergize with the other core FOLFOX drug, 5-fluorouracil, but whether it could also sensitize tumors to oxaliplatin remained an open question.

To answer it, the team turned to two colorectal cancer cell lines, Caco-2 and SW48, both of which harbor wild-type TP53, the form of the gene found in roughly 57 percent of colorectal tumors. Cell viability assays and colony formation experiments showed that ellagic acid on its own suppressed proliferation and, when paired with oxaliplatin, produced a genuinely synergistic effect as measured by combination index analysis. At the concentrations selected for further study, 40 micromolar ellagic acid and 2 micromolar oxaliplatin, the polyphenol inhibited a normal colon epithelial cell line by only about 10 percent, suggesting a therapeutic window. Flow cytometry confirmed that the combination drove the highest rate of apoptosis, while oxaliplatin alone mostly stalled cells at the G2/M checkpoint of the cell cycle.

The mechanistic hunt began with an unbiased approach. Network pharmacology predicted that protein phosphorylation would be the dominant regulatory effect of ellagic acid, and a Human Phospho-Kinase Array then revealed that the compound increased the phosphorylation of p53 and p38 while dampening phosphorylated Erk1/2 and Chk2. That pattern pointed straight at Wip1, the wild-type p53-induced phosphatase 1 encoded by the oncogene PPM1D. Wip1 sits at the center of a negative feedback loop: p53 switches on Wip1 expression, but Wip1 in turn dephosphorylates and silences p53 and inactivates p38. Western blotting confirmed that ellagic acid inhibited Wip1 and boosted p-p53 and p-p38 in a dose-dependent fashion, although molecular docking found no direct binding between the polyphenol and Wip1, meaning the phosphatase was being suppressed indirectly.

The trail led upstream to ATM, the ataxia-telangiectasia mutated kinase that orchestrates the cellular response to DNA double-strand breaks. Surprisingly, ellagic acid inhibited ATM phosphorylation in a dose-dependent manner, while the combination with oxaliplatin enhanced phosphorylation of ATR, a related kinase that serves as a compensatory survival pathway when ATM signaling falters. Molecular docking predicted that ellagic acid binds ATM at the residues SER1801 and ARG2279, and the team verified physical interaction using co-immunoprecipitation with biotin-conjugated ellagic acid and a cellular thermal shift assay, which showed that the compound stabilizes the ATM protein. Genetic experiments sealed the argument: forcing ATM overexpression abolished the synergistic killing by the drug pair, while silencing ATM with shRNA attenuated oxaliplatin resistance, faithfully mimicking the effect of ellagic acid. Blocking the compensatory ATR pathway with the inhibitor M6620 likewise dismantled the synergy, underscoring how both arms of the DNA damage response shape the outcome.

The remaining puzzle was how suppressing ATM, an activator of p53, could still leave p53 empowered. The answer lay in an unexpected metabolic branch: ATM phosphorylates AMPK, which in turn phosphorylates HIPK2 at specific residues. Phosphorylated HIPK2 leaves the nucleus and loses the ability to bind Wip1, allowing Wip1 to escape degradation. When ellagic acid dampens ATM signaling, AMPK phosphorylation falls, HIPK2 stays in the nucleus where it tags Wip1 for ubiquitination and proteasomal destruction, and Wip1 levels collapse. With the brake released, p53 signaling surges, elevating p21 and shifting the Bax/Bcl-2 ratio toward apoptosis. Transfection experiments confirmed each link: overexpressing Wip1 erased the benefit of the combination, while knocking Wip1 down enhanced oxaliplatin’s efficacy on its own.

Clinical and animal data lent the mechanism real-world weight. Among 71 patients with stage III wild-type TP53 colorectal cancer who received postoperative FOLFOX chemotherapy at Tianjin Union Medical Center between 2015 and 2023, high Wip1 expression in tumor tissue correlated significantly with poorer overall and disease-free survival, whereas ATM expression varied little. The team then established patient-derived xenograft models using tumor tissue from three patients, one with high and one with low Wip1 expression. In the Wip1-high model, adding ellagic acid, dosed at 100 or 200 milligrams per kilogram daily alongside oxaliplatin every three days, effectively downregulated Wip1, reactivated p53 and sharpened the antitumor effect measured by Ki-67 and TUNEL staining. In the Wip1-low tumor, the polyphenol added little. The study was candid about safety limits: all mice receiving the highest combination dose died within two weeks from drug toxicity, and hepatic injury appeared when the ellagic acid dose exceeded 160 milligrams per kilogram per day, leading the authors to designate the 100 milligram per kilogram regimen as relatively safe.

The findings carry several caveats that the researchers themselves acknowledge. The work was restricted to wild-type TP53 tumors to avoid confounding, since mutant p53 rewires the Wip1 relationship entirely. Ellagic acid is also metabolized by gut bacteria into urolithin A, which acts through distinct mechanisms, and individuals of the UM-0 metabotype cannot produce urolithin A at all, so the contribution of these metabolites in different patients remains to be clarified. Liquid chromatography-mass spectrometry did confirm that ellagic acid is detectable in the circulation of a patient taking Xihuang Pill, lending clinical plausibility to the adjuvant strategy. Wip1 inhibitors have generally shown weak activity alone but real promise in combination, and this study suggests that Wip1 expression could serve as a biomarker to guide which patients benefit when ATM-targeting agents are added to platinum chemotherapy. If larger studies bear out the safety and synergy, ellagic acid or ellagitannin-rich herbal formulations could become a low-cost adjunct to FOLFOX, precisely tailoring a decades-old regimen to the molecular fingerprint of each patient’s tumor.

Subject of Research: Ellagic acid as a chemosensitizer for oxaliplatin in wild-type TP53 colorectal cancer via the ATM/AMPK/HIPK2/Wip1 pathway

Article Title: Ellagic acid promoted efficacy of oxaliplatin on wild-type TP53 colorectal cancer via regulating ataxia-telangiectasia mutated protein kinase and Wip1

Article References: Zhao, Y., Ma, M., Han, S., Hu, J., Guo, X., Wang, W., Liu, S., Zhao, Z., Qiao, Y., & Wang, Y. (2026). Ellagic acid promoted efficacy of oxaliplatin on wild-type TP53 colorectal cancer via regulating ataxia-telangiectasia mutated protein kinase and Wip1. Frontiers in Pharmacology, 17, Article 1944826. https://doi.org/10.3389/fphar.2026.1944826

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1944826

Keywords: ellagic acid, oxaliplatin, colorectal cancer, ATM kinase, Wip1, p53, PPM1D, chemotherapy resistance, AMPK, HIPK2, patient-derived xenograft, polyphenols

The scale of the analysis sets it apart. The researchers profiled 62 primary pancreatic tumors using single-cell RNA sequencing, capturing the gene-expression fingerprints of 443,451 individual cells. For 11 of those tumors, they added spatial transcriptomics, a technique that preserves the physical location of gene activity across 53,236 tissue spots, allowing the team to see not just which cells existed but where they sat relative to one another. Crucially, the cohort also included matched samples from six tumors collected before and after chemotherapy, providing a rare before-and-after view of how treatment reshapes the cellular landscape of the disease.

Because single-cell RNA sequencing does not directly read DNA, the team inferred the copy-number alterations, gains and losses of chromosomal segments, from expression data, then validated the approach against whole-genome sequencing and confirmed key findings with fluorescence in situ hybridization. Using these inferred genetic signatures as barcodes, they grouped malignant cells into clones and reconstructed evolutionary relationships within each tumor. The result was unambiguous: multiple genetically distinct neoplastic clones coexist within individual tumors, each carrying its own complement of chromosomal alterations and, remarkably, its own transcriptional personality.

That clone-specific personality extends beyond the cancer cells themselves. The analysis revealed that different clones deploy different ligand–receptor programs, the molecular handshakes through which cells communicate with their surroundings, and that these communication programs are modulated by genomic dosage. When a clone carried an amplification of a ligand or receptor gene, the corresponding interactions with neighboring cells were enriched; when the gene was deleted, the interactions were suppressed. In other words, the raw genetic equipment a clone inherits determines the conversations it can hold with the tumor microenvironment. Spatial transcriptomics and multiplex immunofluorescence independently confirmed that these genetically encoded differences are visible in intact tissue, with one validated example being the NECTIN2–TIGIT axis, an immunosuppressive interaction between tumor cells and T cells that was strengthened in clones carrying NECTIN2 copy-number gains.

Perhaps the most striking finding concerns the transition between the two major molecular subtypes of pancreatic cancer, known as classical and basal. Tumors dominated by the classical program tend to respond somewhat better to therapy, while the basal program is associated with aggression and resistance. By integrating the clone-level genetic data with phylogenetic reconstruction, the researchers found that focal amplification of the 8q24 region, which contains the potent oncogene MYC, was recurrently associated with classical-to-basal transitions occurring within tumor lineages at a frequency above chance. These were not separate tumors with different subtypes; they were evolutionary events unfolding inside a single patient’s cancer, in which one branch of the tumor’s family tree switched identity.

The consequences of that switch were equally significant. The clones that underwent the classical-to-basal transition showed a coordinated depletion of immune-response programs, suggesting that as they shifted identity, they also remodeled the local immune environment in ways that shielded them from attack. To test whether MYC was a driver or merely a passenger, the team performed functional perturbation experiments in murine models and primary human tumor-derived systems. When they knocked down MYC, the cells reactivated classical transcriptional programs and restored immune-response pathways. The evidence supports a model in which MYC actively maintains the basal, immune-depleted state, positioning it as a linchpin connecting genome evolution, cell identity and immune evasion.

Spatial analysis added a third dimension to the story. The team identified dispersed clones, malignant populations that spread widely across the tumor rather than forming compact territories, that were enriched for epithelial-to-mesenchymal transition activity, the developmental program that endows epithelial cells with migratory, invasive properties, and for immune-suppressive signaling. These dispersed clones correlated with metastatic potential and were found to colonize lymph node niches, the anatomical way stations through which pancreatic cancer typically begins its deadly spread. The dispersed clones had also shifted toward a basal phenotype, tying together the threads of genetic evolution, transcriptional plasticity and anatomical progression into a single narrative of how the disease advances.

The chemotherapy-matched samples offered a sobering evolutionary perspective. Comparing clones before and after treatment, the researchers documented clones that were eradicated, clones that persisted in expanded, contracted or stable form, and clones that emerged de novo after therapy. Retained clones showed distinct patterns of interaction with lymphatic and stromal cells compared with eradicated ones, and the interactions between specific stromal populations, including inflammatory and myofibroblastic cancer-associated fibroblasts and endothelial cells, differed systematically across the eradicated, pre-treatment retained and post-treatment retained clone groups. Chemotherapy, in this view, is not simply a cytotoxic assault but an evolutionary filter that selects for clones best equipped to survive in a remodeled microenvironment.

The technical achievement underlying these findings deserves emphasis. Distinguishing malignant from normal epithelial cells, assigning cells to clones, deconvolving spatial spots into their constituent cell types and reconstructing phylogenies from noisy single-cell data required an integrated computational pipeline drawing on tools for copy-number inference, cell–cell communication analysis and pathway enrichment. The team validated their copy-number calls against whole-genome sequencing and confirmed spatial relationships with orthogonal imaging, an unusually rigorous level of cross-checking for a single-cell study. The processed data have been deposited in public repositories, and the raw data are available through the database of Genotypes and Phenotypes under controlled access, making the resource available to the wider research community.

For a disease with a five-year survival rate that remains among the lowest of any major cancer, the study’s implications are potentially significant. If the most dangerous properties of pancreatic cancer, immune evasion, subtype switching and metastatic seeding, are properties of specific clones rather than of the tumor as a whole, then therapies could be designed to target the mechanisms those clones exploit. The demonstration that MYC knockdown reverses the basal, immune-depleted state points toward strategies aimed at clonal evolution itself, while the clone-specific ligand–receptor programs suggest that blocking particular tumor–microenvironment interactions could disarm the most aggressive branches of a tumor’s family tree. The authors caution that these are avenues for future investigation rather than ready-made treatments, but the study provides something pancreatic cancer research has lacked: a detailed, spatially resolved map of the enemy’s internal politics, and a demonstration that within that map lie the vulnerabilities that evolution has left exposed.

Subject of Research: Clonal heterogeneity and tumor progression in human pancreatic ductal adenocarcinoma

Article Title: Clonal heterogeneity in human pancreatic ductal adenocarcinoma and its impact on tumor progression

Article References: Kalfakakou, D., Cameron, D. C., Kawaler, E. A., Tsuda, M., Wang, L., Su, Q., Kim, S., Manolakos, E., Jing, X., Hajdu, C., Tamayo, D. L., Shim, Y., Ackermann, A., Weissinger, D., Zimny, H., Hernandez, R., Beier, M., Dimartino, D., Meyn, P., … Simeone, D. M. (2026). Clonal heterogeneity in human pancreatic ductal adenocarcinoma and its impact on tumor progression. Nature Genetics. https://doi.org/10.1038/s41588-026-02779-5

Image Credits: AI Generated

DOI: 10.1038/s41588-026-02779-5

Keywords: pancreatic cancer, single-cell RNA sequencing, spatial transcriptomics, clonal heterogeneity, MYC, tumor microenvironment, epithelial-to-mesenchymal transition, chemotherapy resistance, tumor evolution, immune evasion, copy-number variation, metastasis

The extracellular matrix, long dismissed as little more than biological mortar, has increasingly been recognized as an active participant in tumor biology. In colorectal cancer, the matrix is often remodeled and enriched with fibrillar collagens, creating a dense, stiff environment that can influence how cells sense their surroundings. The Nottingham-led team began by mining publicly available transcriptomic datasets from colorectal cancer patients, including GSE44861 and GSE32323, and found that collagen-associated genes, particularly COL1A1 and COL1A2, which encode the alpha chains of type I collagen, were consistently upregulated in tumors compared with healthy tissue. Immunofluorescence staining of patient tumors confirmed frequent accumulation of collagen I in the tumor microenvironment, and Kaplan-Meier survival analysis linked high collagen I signaling to poorer patient outcomes.

To interrogate these correlations experimentally, the researchers turned to patient-derived organoids, miniature three-dimensional tumor cultures grown from surgical biopsies obtained at Queen’s Medical Centre in Nottingham with ethical approval and patient consent. These organoids preserve the genetic and epigenetic identity of the original tumors, including canonical colorectal cancer alterations such as APC, KRAS and TP53 mutations, making them far more faithful than conventional cell lines. The team embedded organoids in a mixed Matrigel-collagen I matrix, designated MGCOL, and compared them with organoids grown in standard Matrigel alone. Two-photon microscopy using second harmonic generation allowed the researchers to visualize the collagen fibers directly within the living gels, while rheological measurements tracked the mechanical properties of the matrices over nearly a month of culture.

The results were unambiguous. When colorectal cancer organoids were grown in collagen I-enriched matrices, they mounted a robust activation of transforming growth factor beta signaling, a master pathway controlling tissue repair, cell identity and immune modulation. Alongside this, the cells increased their expression of LTBP2, latent transforming growth factor-beta binding protein 2, a secreted extracellular protein that sequesters and regulates TGFβ family ligands. The organoids also activated a partial epithelial-to-mesenchymal transition program, a transcriptional shift in which epithelial cells acquire mesenchymal traits such as motility, invasiveness and stress resistance, without fully abandoning their epithelial character. This partial EMT state is increasingly viewed as a hallmark of aggressive, treatment-refractory tumors.

Crucially, the researchers wanted to know whether these matrix-induced changes would persist once cells left the dish. They transplanted collagen I-primed organoids into xenograft mouse models and found that the resulting tumors retained an EMT-biased, LTBP2-high phenotype with elevated TGFβ pathway activation, as measured by phosphorylated SMAD2 staining. This persistence in vivo suggests that the extracellular matrix does not merely produce transient, reversible changes but can lock tumor cells into alternative identity states that survive transplantation. The finding carries significant implications, because it implies that the matrix composition of a patient’s tumor could pre-condition cancer cells before any drug is administered.

The clinical relevance of the LTBP2 signature was reinforced by analysis of The Cancer Genome Atlas colon adenocarcinoma cohort. LTBP2 expression was significantly elevated in metastatic colorectal cancer compared with primary tumors and healthy colon, and high LTBP2 expression was associated with worse disease-free survival across more than 1,300 patients, with a hazard ratio of 1.41. INHBA, another TGFβ pathway component induced by collagen I, showed an even stronger association, with a hazard ratio of 2.48. LTBP2 expression also correlated strongly with FBN1 and LOXL1, genes involved in elastic fiber assembly and collagen cross-linking, tying the LTBP2 signal directly to matrix remodeling biology.

Perhaps the most consequential discovery concerned chemotherapy. When the researchers treated collagen I-primed and control organoids with 5-fluorouracil, the standard backbone drug for colorectal cancer, the collagen-rich environment markedly enhanced the pro-inflammatory transcriptional response to the drug. Cells in collagen I-rich matrices responded to chemotherapy by ramping up inflammatory signaling programs, including chemokine expression, rather than simply undergoing cell death. Pharmacological inhibition of TGFβ signaling using the TGFβ receptor 1 inhibitor SB431542, or of p38 MAPK signaling using SB202190, modulated this chemotherapy-induced inflammatory program, implicating both pathways as mechanistic links between the matrix and the drug response. In other words, the same scaffold that primes cells toward plasticity also tunes how they react when attacked by cytotoxic therapy.

The authors propose that collagen I establishes a distinct tumor microenvironmental niche in which TGFβ-dependent EMT priming, epithelial plasticity and altered chemotherapy responses converge. Rather than a single driver mutation or a single signaling pathway, treatment resistance may emerge from the interplay between a tumor’s genetic identity and the physical and biochemical properties of its surroundings. This mechanistic framework helps explain why patients with histologically similar tumors can respond so differently to identical regimens, and it suggests that matrix composition, measurable through staining or imaging approaches such as Picrosirius red and second harmonic generation, could serve as a biomarker for treatment stratification.

The study also validates collagen I-enriched organoid cultures as a physiologically relevant platform for studying matrix-tumor interactions, something that standard Matrigel cultures, which lack the fibrillar collagen architecture of real tumors, cannot fully capture. By adjusting matrix composition in a controlled way, researchers can now dissect how individual matrix components shape cell state and drug sensitivity in patient-specific backgrounds. The work was supported by the Medical Research Council, the Royal Society and Research Foundation Flanders, and the authors note that the findings support further investigation of TGFβ and p38 signaling as potential therapeutic targets to overcome matrix-mediated treatment resistance.

For patients, the message is that the terrain around a tumor matters as much as the tumor itself. If collagen I-rich niches prime cancer cells to adapt and inflame rather than die under chemotherapy pressure, then combination strategies that target the matrix or its downstream signaling could sensitize tumors that would otherwise resist treatment. While the research remains at the preclinical stage, resting on organoid and xenograft models rather than clinical trials, it adds colorectal cancer to the growing list of malignancies in which the extracellular matrix is emerging as an active architect of therapeutic failure, and it hands clinicians and drug developers a concrete set of molecular handles, LTBP2, TGFβ and p38, with which to intervene.

Subject of Research: Collagen I-driven extracellular matrix regulation of epithelial plasticity and chemotherapy response in colorectal cancer

Article Title: Patient-derived models reveal LTBP2-linked collagen I niche that prime adaptive cell plasticity and tune chemoresponse in colorectal cancer

Article References: Sagadevan, S., Dalleywater, W., Balasubramanian, B., Okkelman, I. A., Martinez-Espuga, M., Norkin, M., Gall, L., Mendonca, T., Mukherjee, A., Wright, A. J., Dmitriev, R. I., Acheson, A. G., Huelsken, J., Mata, A., Pin, C., & Ordóñez-Morán, P. (2026). Patient-derived models reveal LTBP2-linked collagen I niche that prime adaptive cell plasticity and tune chemoresponse in colorectal cancer. Journal of Experimental & Clinical Cancer Research. https://doi.org/10.1186/s13046-026-03845-w

Image Credits: AI Generated

DOI: 10.1186/s13046-026-03845-w

Keywords: colorectal cancer, collagen I, extracellular matrix, LTBP2, TGF-beta, patient-derived organoids, epithelial-mesenchymal transition, cell plasticity, chemotherapy resistance, 5-fluorouracil, p38 MAPK, tumor microenvironment

The DEK::CAN fusion gene arises from a balanced chromosomal translocation known as t(6;9)(p23;q34), in which segments of chromosomes 6 and 9 swap places and fuse the DEK gene to the CAN gene, also called NUP214. This fusion is found in only about 1 to 2 percent of all acute myeloid leukemia patients, but its presence carries serious consequences. The abnormal protein it produces disrupts nucleoporin function, impairing the carefully regulated transport of molecules between the nucleus and the cytoplasm and scrambling the signal transduction pathways that depend on that traffic. At the same time, the fusion constitutively activates the mTOR signaling pathway, a central growth-control circuit, pushing malignant cells to proliferate relentlessly while blocking the programmed cell death that would normally eliminate damaged cells.

WT1 tells a complementary story. Originally identified as a tumor suppressor in kidney cancer, the gene frequently behaves as an oncogene in blood malignancies, and its overexpression has been detected across myeloid neoplasms including both myelodysplastic syndromes and acute myeloid leukemia. When WT1 is overproduced, it suppresses pro-apoptotic genes such as BAX and aberrantly activates anti-apoptotic pathways including PI3K/AKT, tipping the delicate balance between cell survival and cell death in favor of the malignant clone. This dual action directly promotes the expansion of leukemic cells and fosters resistance to chemotherapy. The Chinese team reasoned that when DEK::CAN and WT1 overexpression occur together, the two abnormalities may synergize across multiple signaling pathways and transcriptional networks, producing a disease that is both highly aggressive and unusually tolerant of standard treatment.

The patient’s clinical course illustrates that synergy in stark terms. Admitted in August 2021 with three days of fatigue and dizziness after months of untreated cytopenia, she presented with profound pancytopenia: a white blood cell count of just 0.68 billion cells per liter, hemoglobin of 35 grams per liter, and platelets of 23 billion per liter. Bone marrow examination revealed a hypercellular marrow packed with 81 percent blasts showing monocytoid features, consistent with acute monocytic leukemia of the AML-M5 subtype. Both the granulocytic and erythroid lineages were severely suppressed, and dysplastic changes were visible across cell lineages, a hallmark of the disease’s myelodysplastic origins. Flow cytometric immunophenotyping confirmed a blast population expressing markers such as CD117, CD13, CD33, CD34, HLA-DR, and aberrant nTDT, while conventional G-banding karyotype analysis of twenty metaphase spreads revealed the telltale 46,XX,t(6;9)(p23;q34) karyotype.

Molecular testing then delivered the findings that set this case apart. A multiplex real-time reverse transcription PCR screening panel covering 56 leukemia-related fusion genes returned a positive result for DEK::CAN, which quantitative PCR verified at a DEK::CAN/ABL ratio of 188.21 percent, an extraordinarily high transcript burden. The same panel measured WT1 mRNA at a WT1/ABL ratio of 52.90 percent, far above the normal reference threshold of 2.5 percent, confirming overexpression. Targeted next-generation sequencing of 22 AML and MDS-related genes added a third layer of complexity: a non-synonymous mutation in exon 6 of the U2AF1 gene, c.467G>A resulting in the p.Arg156His substitution, detected at a variant frequency of 43.30 percent. Notably, no common mutations in FLT3, RAS, IDH2, DNMT3A, or TET2 were found, distinguishing this case from the typical mutational landscape of t(6;9) leukemia.

The U2AF1 mutation may be the key to understanding why this case was so aggressive. Recent research has shown that both DEK and WT1 physically interact with the U2AF1/U2AF2 heterodimer, the core spliceosome component that governs alternative splicing, the process by which RNA transcripts are cut and reassembled into different protein-coding forms. Both oncogenes can therefore influence the splicing of numerous genes involved in hematopoietic differentiation and chemotherapy resistance. Because the patient’s U2AF1 mutation alters the very protein that DEK and WT1 engage, the researchers suggest it may have enhanced or synergized with the fusion gene and WT1 overexpression in corrupting RNA splicing. Combined with HOX gene reprogramming, evasion of apoptosis, and chemotherapy tolerance, this triple hit could plausibly shape the exceptionally aggressive phenotype observed.

Treatment followed established guidelines for high-risk AML. Classified as high risk based on the t(6;9) karyotype and DEK::CAN positivity, the patient received two cycles of intensive induction chemotherapy with the IA regimen of idarubicin and cytarabine beginning in late August 2021. The first cycle failed to achieve remission, leaving bone marrow blasts at 25.5 percent, but the second cycle brought blasts down to 2 percent with normalized blood counts, achieving complete remission. Because acute monocytic leukemia carries a heightened risk of central nervous system relapse, she underwent lumbar puncture with intrathecal chemotherapy, followed by three cycles of intermediate-dose cytarabine consolidation. Along the way she endured a pulmonary fungal infection, Klebsiella pneumoniae sepsis, and Gram-negative bacterial sepsis, all controlled with anti-infective therapy, and experienced a transient period of remission with incomplete hematologic recovery before regaining full remission in February 2022.

Yet the marrow’s response told only half the story. After the third consolidation cycle, the patient developed severe myelosuppression with a platelet count plummeting to 19 billion per liter. In the early morning of February 22, 2022, she suddenly lost consciousness and was found with bloody vomitus; resuscitation failed and she died. Clinicians suspected fatal bleeding, possibly gastrointestinal, intracranial, or pulmonary, though no autopsy was performed to confirm the cause. Critically, the recurrent infections and cumulative chemotherapy toxicity had prevented her from ever undergoing allogeneic hematopoietic stem cell transplantation, the intervention that published data identify as the single most important determinant of survival in DEK::CAN-positive disease. Her marrow remained in morphologic remission at the time of her death, a dissociation between molecular response and clinical tolerability that the authors describe as the case’s most sobering lesson.

The literature reinforces that lesson with hard numbers. A multicenter study of 107 patients with t(6;9)/DEK-NUP214-positive myeloid neoplasms found that patients who received allogeneic transplantation had a median overall survival of 62 months and an estimated five-year survival of roughly 40 to 50 percent, while non-transplanted patients had a median survival of only 17 months and a five-year survival approaching zero. Chemotherapy alone, in other words, yields five-year survival of just 0 to 5 percent. The present patient’s approximately 12-month survival without transplantation falls squarely within that non-transplant experience. A separate molecular study of nine patients with isolated t(6;9) disease found that 83 percent carried at least one somatic mutation and reported a median overall survival of only 20 months, underscoring how uniformly poor the outlook remains for this cytogenetic subgroup.

The authors draw several practical conclusions from the case. All newly diagnosed myelodysplastic syndrome patients should routinely undergo karyotype analysis and DEK::CAN fusion gene screening, since the fusion’s presence fundamentally alters prognosis and treatment planning. Once any form of remission is achieved, whether complete remission or remission with incomplete hematologic recovery, transplantation should be bridged promptly under controlled infection and adequate organ function, without waiting for full blood count recovery. For patients rendered ineligible by toxicity, the case points toward emerging low-toxicity alternatives: preclinical studies show that mTOR inhibitors such as everolimus can suppress the growth of DEK::CAN-positive cells, and WT1-targeted immunotherapy is under development. Dynamic monitoring of WT1 levels before treatment, after chemotherapy, and around transplantation is also recommended, since persistent WT1 elevation predicts relapse. The team acknowledges the limitations inherent in a single case report, including the unknown status of the fusion gene at the original MDS diagnosis and the absence of autopsy, but the message for clinicians is unambiguous: in this rare leukemia, the enemy is not only the disease itself but the window of time that complications can close before the cure can be delivered.

Subject of Research: A rare case of myelodysplastic syndrome-transformed acute myeloid leukemia with concurrent DEK::CAN fusion gene positivity and WT1 overexpression

Article Title: Myelodysplastic Syndromes‐Transformed Acute Myeloid Leukemia With Concurrent DEK::CAN Fusion Gene Positivity and WT1 Overexpression: A Case Report and Literature Review

Article References: Mao, W., Zhou, T., Xu, X., Luo, S., Jiang, S., & Yu, Z. (2026). Myelodysplastic Syndromes‐Transformed Acute Myeloid Leukemia With Concurrent DEK :: CAN Fusion Gene Positivity and WT1 Overexpression: A Case Report and Literature Review. Cancer Reports, 9(10), Article e70714. https://doi.org/10.1002/cnr2.70714

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DOI: 10.1002/cnr2.70714

Keywords: acute myeloid leukemia, myelodysplastic syndromes, DEK::CAN fusion gene, WT1 overexpression, U2AF1 mutation, chromosomal translocation, allogeneic stem cell transplantation, mTOR pathway, alternative splicing, chemotherapy resistance, hematologic malignancy, case report