Researchers treated collagen-induced arthritis rats with quercetin or methotrexate for 28 days, while normal rats provided a baseline. The assessment covered arthritis scores, hind-paw volume, inflammatory cytokines, bone-related measures, joint damage and Wnt3A and β-catenin expression. Compared with normal rats, the arthritic animals had higher arthritis scores, greater hind-paw swelling and elevated levels of the pro-inflammatory cytokines TNF-α, IL-1β, IL-6 and IL-17A.

The collagen-induced arthritis group also showed reduced bone mineral density, bone volume fraction, trabecular thickness and trabecular number, together with severe joint damage. According to the abstract, quercetin intervention alleviated clinical symptoms, improved bone microarchitecture, restored cytokine balance and substantially downregulated Wnt3A and β-catenin at both the messenger RNA and protein levels in the spleen and joints. The reported improvements in bone microarchitecture were comparable to those achieved with methotrexate in the experiment. Quercetin also did not induce observable hepatorenal toxicity under the study’s testing conditions.

These findings are limited to the reported rat experiment and to the outcomes described in the available abstract, which was presented as a subscription preview rather than the full article. The parallel changes in pathway expression, inflammation and bone measures support a possible mechanistic association, but they do not prove a direct causal relationship. The results therefore provide a basis for further investigation and do not demonstrate that quercetin is safe or disease-modifying in people with rheumatoid arthritis.

Subject of Research: Quercetin effects on bone erosion, inflammation and Wnt3A/β-catenin expression in collagen-induced arthritis rats

Article Title: Quercetin ameliorates rheumatoid arthritis-associated bone erosion via inhibiting the Wnt3a/β-catenin signaling axis

Article References: Shen, T., Liang, R., Liang, M., Guo, Q., & Pang, Q. (2026). Quercetin ameliorates rheumatoid arthritis-associated bone erosion via inhibiting the Wnt3a/β-catenin signaling axis. Molecular Biology Reports, 53(1), Article 1575. https://doi.org/10.1007/s11033-026-12740-8

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12740-8

Keywords: quercetin, collagen-induced arthritis, bone erosion, bone microarchitecture, Wnt3A, β-catenin, rheumatoid arthritis, inflammation, methotrexate, animal study, ameliorates, rheumatoid

Angiogenesis is the physiological formation of blood vessels that supplies cells with oxygen and nutrients. It is carried out by endothelial cells, the innermost layer of blood vessels, and depends on pro-angiogenic growth factors, cell-adhesion proteins, and signaling pathways. These pathways regulate different stages of vessel formation, including endothelial-cell proliferation, differentiation, migration, polarity, and survival.

In tumors, dysregulation of these pathways can contribute to uncontrolled angiogenesis, according to the review. The paper examines how VEGF, β-catenin, VE-cadherin, and integrin are associated with Wnt–β-catenin signaling in this process. Wnt–β-catenin signaling is presented as an important pathway for cell proliferation.

The review notes that anomalous activity in this pathway can enhance the expression of pro-angiogenic genes, including VEGF and fibronectin. Within the authors’ model, β-catenin, VE-cadherin, and integrin form an interconnected signaling triad associated with angiogenesis. SFRP4 enters this proposed network because it is a Wnt antagonist with established anti-tumorigenic, anti-angiogenic, and pro-apoptotic roles.

The review’s central proposal is that SFRP4 may act on integrin in a way that disrupts Wnt signaling and thereby inhibits angiogenesis. This extends the proposed connection between SFRP4 and integrin into an explanation for how the Wnt pathway and the broader angiogenic network may interact in tumors. Instead, it reviews angiogenic factors and organizes them into a conceptual model centered on the interplay among SFRP4, integrin, β-catenin, VE-cadherin, and VEGF.

The supplied abstract describes the SFRP4–integrin interaction as a novel proposed role and states that it could disrupt Wnt signaling and inhibit angiogenesis. The available evidence supports the established biological roles summarized by the authors, while the mechanism connecting SFRP4 directly to integrin remains a hypothesis presented by the review. Accordingly, the work provides a framework for understanding possible regulation of the tumor angiogenic loop, but the supplied material does not support claims about human efficacy or clinical application.

The review was published in Medical Oncology in 2026 as volume 43, article 340.

Subject of Research: Proposed SFRP4–integrin regulation of Wnt–β-catenin signaling in tumor angiogenesis

Article Title: The interplay of integrin, VE-cadherin, and β-catenin signaling triad in angiogenesis: regulation by Wnt antagonist, secreted frizzled related protein 4 in the tumor angiogenic loop

Article References: Janaki P, A., Gamit, N., Agarwal, P., Dharmarajan, A., & Warrier, S. (2026). The interplay of integrin, VE-cadherin, and β-catenin signaling triad in angiogenesis: regulation by Wnt antagonist, secreted frizzled related protein 4 in the tumor angiogenic loop. Medical Oncology, 43(11), Article 340. https://doi.org/10.1007/s12032-026-03443-y

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03443-y

Keywords: SFRP4, tumor angiogenesis, integrin, Wnt signaling, β-catenin, VE-cadherin, VEGF, endothelial cells, cancer biology, mechanistic review, interplay, catenin

The investigation was designed around a possible link between Wnt/β-catenin signaling, stem-like cellular characteristics and chemoresistance. The canonical pathway promotes cancer-stem-cell renewal, proliferation and differentiation, while its activation has also been associated with epithelial–mesenchymal transition and metastatic dissemination in earlier colorectal cancer research cited by the authors. Wnt/β-catenin activity may arise through mutations affecting β-catenin or proteins in its destruction complex, as well as through overexpression of Wnt ligands, Frizzled receptors or Dkk-1. Because the pathway has been associated with both tumor progression and therapeutic failure, the researchers examined whether it was active in their established model of long-term 5-FU resistance.

The experimental system consisted of parental HCT-116 colorectal cancer cells and HCT-116 5FUR cells derived through long-term exposure to 5-FU. Previous work with this model had shown that the resistant cells acquired epithelial–mesenchymal transition characteristics together with enhanced migration and invasion. The current study did not determine whether stemness and epithelial–mesenchymal transition are controlled by the same signaling mechanism. Its narrower objective was to measure Wnt/β-catenin activity in the resistant cells, assess selected stemness markers and test whether pharmacological pathway inhibition could make the resistant population more sensitive to 5-FU.

The researchers first used bioinformatic analysis to examine the relationship between two gene signatures in 275 colon cancer samples available through the GEPIA2 platform from The Cancer Genome Atlas. The 5-FU-resistance signature included genes associated with resistance, DNA-damage repair and 5-FU metabolism, while the cancer-stem-cell signature included CD44, PROM1, EPCAM, KLF4, MYC, STAT3, SALL4 and ALDH1A1. Pearson analysis found a positive correlation between the signatures, with R = 0.41 and p < 0.001. This is an association in patient-derived expression data rather than evidence that either signature causes treatment failure, but it provided the clinical-sample context for the subsequent cell experiments.

Laboratory assays showed that the thawed HCT-116 5FUR cells retained their resistant phenotype after recovery from frozen storage. In MTT viability measurements performed 48 hours after exposure to increasing concentrations of 5-FU, the resistant cells tolerated substantially more drug than the parental line. Reverse-transcription quantitative PCR also detected differences in stemness-associated transcripts. ALDH1A1 expression was significantly higher in the resistant cells, whereas POU5F1 showed an upward trend that did not meet the study’s threshold for statistical significance, with p = 0.08. ALDH1A1 was therefore treated as evidence of a stem-like characteristic in this model, not as proof that the entire resistant population consisted of cancer stem cells.

Several measurements indicated stronger canonical Wnt/β-catenin signaling in the 5-FU-resistant cells. Western blotting detected higher levels of both total β-catenin and active, dephosphorylated β-catenin in HCT-116 5FUR cells than in parental cells. Total glycogen synthase kinase 3 beta, or GSK-3β, was lower in the resistant population, while the measured phosphorylated GSK-3β at serine 9 did not differ between the groups. Immunofluorescence imaging likewise showed greater total and active β-catenin staining in the cytoplasm and nuclei of the resistant cells. A TCF/LEF luciferase reporter showed greater β-catenin-dependent transcriptional activity in HCT-116 5FUR cells, and cyclin D1 protein levels were also higher. Taken together, these findings associated the acquisition of 5-FU resistance in this cell line with increased pathway activity.

To test whether that activity contributed to resistance, the investigators used LF3, a 4-thiourea benzenesulfonamide derivative that inhibits the interaction between β-catenin and TCF4. Its negatively charged sulfonamide group binds to Lys435 on β-catenin and competitively prevents the interaction with Asp16 in TCF4, blocking downstream pathway activation. The researchers selected this downstream strategy because colorectal cancer mutations in APC, RNF43 or AXIN2 can generate truncated proteins and constitutive pathway activation, which may limit approaches aimed only at upstream components. In the resistant cells, 60 µM LF3 reduced relative TCF/LEF luciferase activity by approximately sixfold after 24 hours and also reduced cyclin D1 protein levels, confirming both functional pathway inhibition and a downstream molecular effect.

LF3 at the concentration used for pathway blockade did not by itself eliminate the resistant cells. After 48 hours, the maximum tested concentration of 60 µM reduced viability by approximately 30% in both parental and resistant cultures. The LF3 half-maximal inhibitory concentration was 103.5 µM in HCT-116 cells and 135.2 µM in HCT-116 5FUR cells. Combination experiments showed a different effect. The 5-FU IC50 in the resistant cells was 4.8 µM, compared with 0.035 µM in the parental line, documenting the large shift associated with long-term resistance. Adding LF3 lowered the 5-FU IC50 in HCT-116 5FUR cells to 0.138 µM and further reduced viability in the combination condition.

The authors interpret these measurements as evidence that Wnt/β-catenin activity regulates cellular events involved in chemoresistance and that blocking the pathway can impair the resistant phenotype in this model. The stemness and epithelial–mesenchymal transition findings came from separate analyses, so the study did not establish that the two phenotypes are interconnected. The authors propose that cells in intermediate epithelial–mesenchymal states may acquire stem-like characteristics when canonical Wnt signaling is active, but that mechanism was not directly tested here. They also identify long-term 5-FU-resistant cellular models as experimental systems for examining resistance, epithelial–mesenchymal transition and stemness within the same framework.

The scope of the evidence limits how the findings can be interpreted. All experimental results came from the HCT-116 5FUR cell model, while the patient-data analysis established only a correlation between gene signatures. The study did not assess LF3 safety, pharmacokinetics, effects on normal tissues or clinical outcomes, and it did not test combination treatment in animals, organoids or people. The measured result is therefore confined to cultured colorectal cancer cells: LF3 inhibited Wnt/β-catenin transcriptional activity, lowered cyclin D1 and made long-term 5-FU-resistant cells more sensitive to 5-FU in viability assays. The work identifies Wnt/β-catenin inhibition as a candidate combination approach for further preclinical evaluation, but the efficacy and clinical applicability of that approach remain unestablished.

Subject of Research: Wnt/β-catenin inhibition and 5-fluorouracil resistance in a colorectal cancer cell model.

Article Title: Pharmacological inhibition of the canonical Wnt/β-catenin signaling pathway sensitizes 5-fluorouracil-resistant colorectal cancer cells

Article References: Ramos, D. A. A., de Pina, D. F. T., Sousa-Squiavinato, A. C. M., de Araújo, W. M., Rocha, M. R., & Morgado-Diaz, J. A. (2026). Pharmacological inhibition of the canonical Wnt/β-catenin signaling pathway sensitizes 5-fluorouracil-resistant colorectal cancer cells. Molecular Biology Reports, 53(1), Article 1522. https://doi.org/10.1007/s11033-026-12711-z

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12711-z

Keywords: colorectal cancer, 5-fluorouracil resistance, Wnt signaling, β-catenin, LF3 inhibitor, cancer stem cells, HCT-116 cells, chemotherapy sensitization, TCF4, preclinical research, Pharmacological, inhibition

The rationale for the study rests on a well-documented clinical observation. A high prevalence of concurrent PIK3CA and CTNNB1 mutations has been reported among patients with endometrial cancer, yet the functional relationship between the two pathways these genes control has remained murky. PIK3CA drives the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) cascade, a growth-promoting network that has long attracted drug developers. CTNNB1, which encodes β-catenin itself, feeds into the Wnt pathway, a transcriptional program implicated in development and, when dysregulated, in numerous cancers. Whether these two axes cooperate to fuel tumor growth, or whether one could be exploited therapeutically against the other, was an open question.

To answer it, the team assembled a panel of eleven endometrial cancer cell lines and tested three mechanistically distinct inhibitors: ICG-001, which blocks the interaction between β-catenin and its transcriptional co-activator CBP; ipatasertib, an AKT inhibitor; and rapamycin, a classic mTOR inhibitor. The results were strikingly asymmetric. ICG-001, but not the PI3K/AKT/mTOR pathway inhibitors, exhibited potent antiproliferative activity specifically in the cells harboring both CTNNB1 and PIK3CA mutations. In other words, the very pathway combination that had seemed like an obvious target for dual blockade turned out to be most vulnerable to a single intervention on the Wnt side.

Transcriptomic profiling helped explain why. When the double-mutant cells were treated with ICG-001, a series of canonical β-catenin target genes were downregulated, confirming that the drug was doing what it was designed to do at the transcriptional level. But the more revealing finding was what appeared in their place: signature genes related to proteotoxic stress and proteostasis disruption were significantly enriched. Proteostasis, the cellular system that governs the synthesis, folding, and disposal of proteins, is a delicate balance. Its collapse is a recognized form of lethal stress in cancer cells, and the gene expression data suggested that ICG-001 was pushing the double-mutant cells precisely in that direction.

The mechanistic follow-up experiments painted a vivid picture of a cell in crisis. ICG-001 treatment induced de novo protein synthesis, meaning the cells began churning out new proteins at an accelerated rate. At the same time, the researchers observed autophagosome formation, detectable as accumulation of the lipidated form of the protein LC3B (LC3B-II), a hallmark of the cell’s attempt to digest and recycle its own contents. Endoplasmic reticulum expansion, another sign of protein-folding overload, was evident, along with the accumulation of ubiquitinated proteins, the molecular equivalent of garbage piling up faster than the cell’s disposal machinery can clear it. Together, these changes indicate severe proteostasis collapse, a state in which the cell’s protein economy fails catastrophically.

What makes this mechanism particularly compelling is the selectivity. The double-mutant cells appear to be running their protein production machinery close to capacity, perhaps because the combined PIK3CA and CTNNB1 mutations impose unusual demands on translation and folding. When ICG-001 disrupts β-catenin/CBP-dependent transcription, the resulting imbalance between protein synthesis and protein quality control becomes lethal specifically for cells with this genetic background, while sparing cells that lack the double mutation. This kind of synthetic vulnerability, where a drug exploits a weakness created by a specific combination of mutations, is the holy grail of precision oncology, because it promises efficacy with a built-in therapeutic window.

The in vitro findings translated into animal models. Daily administration of ICG-001 demonstrated robust antitumor efficacy in xenograft models of CTNNB1/PIK3CA double-mutant endometrial cancer, meaning tumors grown from the double-mutant cells in mice shrank or stopped growing under treatment. Critically, examination of the xenograft tissues revealed marked ubiquitin accumulation, mirroring the proteostasis collapse seen in cultured cells and confirming that the same mechanism operates in living tumors. This consistency between cell culture and animal data strengthens the case that the observed vulnerability is not an artifact of the laboratory dish but a genuine biological dependency of these tumors.

The study also carries a cautionary message for the alternative strategy. Inhibitors of the PI3K/AKT/mTOR pathway have been extensively developed and tested across many tumor types, with mixed results, and the finding that ipatasertib and rapamycin failed to show preferential activity against the double-mutant endometrial cancer cells suggests that simply attacking the PIK3CA-driven arm of the network may not be the right approach for this subset. The interplay between the two pathways, whatever its details, does not make the PI3K axis the Achilles’ heel. Instead, the data redirect attention toward β-catenin/CBP inhibition as the more productive point of attack.

For patients, the implications are significant but tempered by the usual caveats of preclinical research. ICG-001 is an experimental tool compound, and the path from xenograft efficacy to an approved medicine involves medicinal chemistry optimization, safety profiling, and clinical trials in appropriately selected patients. The study nonetheless establishes a clear biomarker strategy: tumors carrying both PIK3CA and CTNNB1 mutations, identifiable through routine genomic sequencing, would be the candidate population for β-catenin-targeted therapy. Given the high prevalence of this double-mutation pattern in endometrial cancer, the addressable patient group could be substantial, offering hope in a disease where advanced-stage options are currently limited largely to chemotherapy, hormone therapy, and, more recently, immunotherapy for a subset of tumors.

The work also adds to a growing appreciation of proteostasis as a therapeutic target in cancer. Drugs that overload the protein-folding and degradation machinery, such as proteasome inhibitors in multiple myeloma, have already proven that stressing this system can be clinically effective. The present study suggests that transcriptional modulation of β-catenin can trigger a similar collapse in a genetically defined solid tumor, extending the concept into gynecologic oncology. As the authors and their collaborators at the National Cancer Center and the University of Tokyo note, these preclinical findings collectively highlight the vulnerability of PIK3CA/CTNNB1 double-mutant endometrial cancers to β-catenin inhibition and establish β-catenin/CBP inhibitors as a promising targeted therapeutic strategy for this specific genetic subset. Clinical validation will take years, but the study provides the mechanistic foundation and the biomarker logic needed to begin that journey.

Subject of Research: Therapeutic potential of β-catenin inhibition in PIK3CA/CTNNB1 double-mutant endometrial cancer

Article Title: Potential of β-catenin inhibitors as a novel therapeutic strategy for PIK3CA/CTNNB1 double-mutant endometrial cancer

Article References: Nakao, T., Kamata, R., Saito, H., Yamamoto, G., Morita, T. Y., Kinoshita, K., Takahashi, Y., Mashima, C., Yamauchi, T., Sakae, Y., Kamii, M., Nakai, K., Hakozaki, Y., Nakajima, H., Harano, K., Naito, Y., Mukohara, T., & Ohashi, A. (2026). Potential of β-catenin inhibitors as a novel therapeutic strategy for PIK3CA/CTNNB1 double-mutant endometrial cancer. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03321-6

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03321-6

Keywords: endometrial cancer, β-catenin, CTNNB1, PIK3CA, Wnt signaling, ICG-001, proteostasis, targeted therapy, xenograft models, PI3K/AKT/mTOR, proteotoxic stress, precision oncology

Ovarian microcystic stromal tumor is exceptionally rare. Since it was first delineated as a distinct entity, only a limited number of cases have been documented in the medical literature worldwide. The tumor belongs to the broad family of ovarian stromal neoplasms, which arise from the supportive tissue of the ovary rather than from the egg cells themselves. What distinguishes MCST is its striking microscopic appearance: the tumor is composed of sheets and nests of relatively uniform cells arranged around a network of tiny, fluid-filled microcysts that give the lesion its name. Under the microscope, this architecture can resemble other ovarian tumors, including yolk sac tumor or even certain metastatic cancers, which historically made diagnosis challenging.

The key to recognizing MCST lies in its immunohistochemical fingerprint. Tumor cells in these lesions characteristically show nuclear expression of β-catenin, a protein that serves as a hallmark feature and helps separate MCST from its many microscopic mimics. The tumors also typically express Cyclin D1, CD10, vimentin, WT1, FOXL2, and SF1, a constellation of markers that pathologists use to confirm the diagnosis and to exclude other possibilities. Despite this growing list of identifying features, the biological behavior and molecular underpinnings of MCST remain incompletely characterized, largely because so few cases exist to study. Most reported tumors have behaved in a benign fashion, and conservative surgical management has generally proven sufficient.

The newly reported case involved a 38-year-old woman who had never been pregnant and who carried a history of irregular menstruation. Her ovarian mass was discovered incidentally, meaning it was found without the patient having shown symptoms directly attributable to the tumor. An initial intraoperative frozen-section examination pointed to a benign sex cord-stromal tumor, allowing the surgical team to proceed with a laparoscopic tumor enucleation, a fertility-sparing approach in which the tumor is shelled out while the ovary is preserved. This minimally invasive strategy reflects the growing recognition that, in carefully selected patients with apparently benign ovarian lesions, organ-preserving surgery can offer excellent outcomes without the need for more radical procedures.

Definitive histopathological examination confirmed the diagnosis of microcystic stromal tumor. The tumor displayed the characteristic morphology and the expected immunoprofile, with positivity for β-catenin, Cyclin D1, CD10, vimentin, WT1, FOXL2, and SF1. But two findings set this case apart. First, the tumor cells showed partial positivity for S100, a calcium-binding protein commonly expressed in neural, melanocytic, and certain other tissues, and one that is not typically associated with MCST. Second, and perhaps more strikingly, the tumor exhibited what the authors describe as a distinctive hormone receptor signature: androgen receptor was strongly expressed in approximately 90 percent of tumor cell nuclei, while progesterone receptor was weak, present in only about 15 percent of cells.

Androgen receptor expression in ovarian tumors carries particular interest because the androgen receptor participates in signaling pathways relevant to ovarian physiology and ovarian carcinogenesis. Its strong expression in this MCST raises questions about whether hormone signaling might play a role in the growth or regulation of these tumors, or whether the finding represents an incidental epiphenomenon without clinical consequence. Similarly, S100 expression introduces a diagnostic wrinkle: S100 positivity can suggest alternative diagnoses, including neural tumors or melanocytic lesions, and its partial presence in an otherwise classic MCST underscores the importance of interpreting immunohistochemical panels in context rather than relying on any single marker. Although androgen receptor expression has been reported in MCST before, and focal S100 positivity has been documented in at least one prior case, the co-existence of both features in a single tumor has only rarely been recorded.

The clinical course of the patient adds a reassuring dimension to the report. Following her laparoscopic enucleation, she recovered well, and follow-up at 28 months revealed no evidence of recurrence. This outcome is consistent with the prevailing understanding of MCST as a typically indolent neoplasm, and it supports the feasibility of conservative surgery combined with careful long-term surveillance in affected patients. For a young woman whose tumor was detected before any malignant transformation or complication, the preservation of ovarian tissue represents a meaningful quality-of-life benefit, and the extended recurrence-free follow-up provides additional confidence in the benign trajectory of this tumor type.

The authors of the report paired their case with a review of the existing literature, aiming to consolidate what is known about the clinicopathological features of MCST and its unusual immunophenotypic variants. Because the entity is so rare, individual case reports effectively serve as the primary source of knowledge, each one contributing data points that slowly refine the diagnostic criteria and the understanding of biological behavior. The review situates the present case within this accumulating record, noting both the consistency of core features—microcystic architecture, nuclear β-catenin, and benign behavior—and the variability in secondary findings such as hormone receptor status and unexpected marker expression.

The report also highlights the practical implications for diagnostic pathology. Pathologists confronting an ovarian microcystic lesion must distinguish MCST from a differential diagnosis that includes yolk sac tumor, juvenile granulosa cell tumor, and clear cell carcinoma, among others. Unusual immunostaining results, such as partial S100 positivity, could easily send the diagnostic workup down an erroneous path if not weighed against the full morphological and immunophenotypic picture. Cases like this one, in which atypical marker expression arises within an otherwise typical tumor, help calibrate the diagnostic thresholds that practicing pathologists apply, reducing the risk of both overdiagnosis and missed diagnosis.

For now, the biological significance of the combined androgen receptor and S100 expression observed in this tumor remains unresolved. The authors emphasize that larger case series will be needed to determine whether such immunophenotypic variation carries any prognostic or therapeutic relevance, or whether it simply reflects the natural heterogeneity of a rare neoplasm. In the meantime, the case stands as a reminder of how much remains to be learned about even the quietest corners of tumor biology—and of how a single carefully documented patient can meaningfully advance the field. The 28-month disease-free outcome offers comfort to patients facing similar diagnoses, while the unusual molecular profile offers scientists a fresh line of inquiry into the mechanisms that drive this enigmatic ovarian tumor.

Subject of Research: A rare benign ovarian stromal neoplasm exhibiting an atypical immunophenotype with androgen receptor and partial S100 expression

Article Title: Ovarian microcystic stromal tumor with unusual expression of AR and partial S100: a case report and literature review

Article References: Liu, M., Sun, Y., Yin, J., Liu, K., & Jiang, Z. (2026). Ovarian microcystic stromal tumor with unusual expression of AR and partial S100: a case report and literature review. Journal of Ovarian Research. https://doi.org/10.1186/s13048-026-02276-7

Image Credits: AI Generated

DOI: 10.1186/s13048-026-02276-7

Keywords: ovarian tumor, microcystic stromal tumor, MCST, androgen receptor, S100, β-catenin, immunohistochemistry, sex cord-stromal tumor, case report, ovarian pathology, laparoscopic surgery, Journal of Ovarian Research

Hepatocellular carcinoma, or HCC, is one of the leading causes of cancer-related death worldwide, and its molecular landscape has been mapped in increasing detail over the past decade through large-scale sequencing efforts. Among the recurrent alterations identified in human HCC samples, mutations in CTNNB1 and in the TERT promoter stand out for their exceptionally high frequency. CTNNB1 mutations stabilize the β-catenin protein, allowing it to escape degradation, accumulate in the cell nucleus and drive the expression of proliferation-promoting genes. TERT promoter mutations, meanwhile, create binding sites for transcription factors that boost expression of telomerase reverse transcriptase, the enzyme that rebuilds chromosome ends and grants cells the replicative immortality that cancer demands. Despite the well-documented prevalence of both alterations, the functional consequences of their co-occurrence had remained poorly understood, leaving a significant gap in the mechanistic picture of how liver tumors arise.

To begin closing that gap, the research team first turned to publicly available data from The Cancer Genome Atlas, or TCGA, a comprehensive genomic database of human tumors. Their statistical analysis of HCC samples revealed a significant association between mutations in CTNNB1 and mutations in the TERT promoter, with a Fisher’s exact test yielding a P value below 0.01. In practical terms, this means that liver tumors carrying one of these alterations are significantly more likely than chance alone would predict to carry the other as well. Such non-random co-occurrence is a classic signature of cooperating cancer genes: when two alterations appear together more often than expected, it typically suggests that their combined effect confers a selective growth advantage that natural selection within the tumor favors strongly.

Association, however, is not causation. To test whether β-catenin and TERT genuinely cooperate in driving liver cancer, the researchers employed an elegant and rapid animal modeling technique known as hydrodynamic tail vein injection, or HTVI. This method involves injecting plasmid DNA into the bloodstream of mice in a way that delivers the genetic material directly into hepatocytes, the main functional cells of the liver, allowing researchers to express specific oncogenes in liver tissue and monitor tumor development over time. The team constructed plasmids encoding a constitutively active form of β-catenin, called Δ90 β-catenin, which carries a deletion that prevents its degradation, alongside plasmids encoding TERT itself.

The results of these experiments were striking. When Δ90 β-catenin and TERT were coexpressed in mouse livers, the animals developed hepatocellular carcinoma rapidly, with tumors emerging far sooner and more abundantly than in any of the control conditions. In contrast, expression of Δ90 β-catenin alone produced only minimal tumor formation, and expression of TERT alone produced essentially no tumors at all. This pattern is the hallmark of oncogenic synergy: neither alteration is sufficient on its own to transform liver tissue, but together they unleash a potent cancer-driving program. The finding provides a functional explanation for the genetic co-occurrence observed in human patient data, and it suggests that the two mutations are not merely passengers traveling together but active collaborators in hepatocarcinogenesis.

With the synergy established, the researchers turned their attention to the molecular mechanism underlying it. Using immunohistochemistry, a technique that detects specific proteins in tissue sections, they examined the tumors induced by combined β-catenin and TERT expression and looked for signs of activated signaling cascades. What they found was strong phosphorylation of ERK1/2, the terminal kinases of the MAPK/ERK pathway, a central signaling cascade that transmits growth-promoting signals from the cell surface to the nucleus. ERK1/2 phosphorylation is a well-established readout of MAPK/ERK pathway activation, and its robust presence in the β-catenin and TERT-driven tumors indicated that this pathway had been switched on in the tumor cells.

To determine whether this pathway activation was merely a byproduct of tumorigenesis or an essential driver of it, the researchers performed a genetic knockdown experiment targeting MEK1/2, the upstream kinases responsible for phosphorylating ERK1/2. When MEK1/2 expression was suppressed in the mouse livers receiving the β-catenin and TERT plasmids, tumor formation was markedly reduced. This loss-of-function experiment confirmed that MAPK/ERK signaling is not incidental but indispensable for the oncogenic cooperation between β-catenin and TERT. In other words, without the MAPK/ERK cascade, the two cancer genes lose their combined power to transform liver tissue, identifying the pathway as a critical dependency of this tumor subtype.

The clinical implications of these findings are considerable. The MAPK/ERK pathway is already a major focus of drug development across many cancer types, and a range of inhibitors targeting components of the cascade, including MEK inhibitors, have been developed and tested clinically. The new study suggests that patients whose liver tumors harbor both CTNNB1 and TERT promoter mutations may represent a molecular subtype that is particularly dependent on MAPK/ERK signaling, and therefore potentially responsive to therapies that target this cascade. Genomic testing for the co-occurrence of these two mutations could, in principle, help identify patients most likely to benefit from such an approach, although the researchers emphasize that their work is preclinical and that translating the findings into patient treatment will require further study.

Beyond its therapeutic implications, the study fills an important conceptual void in liver cancer biology. β-catenin is classically understood as a transcriptional co-activator in the Wnt signaling pathway, and TERT as a guardian of chromosome integrity, so the demonstration that their cooperation routes through MAPK/ERK activation reveals an unexpected layer of crosstalk between these canonical systems. The work was supported by grants from the National Research Foundation of Korea and approved by the Animal Policy and Welfare Committee of Kyung Hee University. As sequencing of liver tumors becomes increasingly routine in clinical practice, mechanistic studies like this one, which connect specific mutation combinations to druggable signaling dependencies, will become ever more essential to realizing the promise of precision oncology in hepatocellular carcinoma.

Subject of Research: Cooperation between TERT promoter mutations and β-catenin activation in hepatocellular carcinoma development via MAPK/ERK signaling

Article Title: Telomerase reverse transcriptase (TERT) accelerates β-catenin-driven hepatocarcinogenesis via MAPK/ERK pathway activation

Article References: Park, H., Lee, J., Moon, H., & Ro, S. W. (2026). Telomerase reverse transcriptase (TERT) accelerates β-catenin-driven hepatocarcinogenesis via MAPK/ERK pathway activation. Cancer Cell International. https://doi.org/10.1186/s12935-026-04329-9

Image Credits: AI Generated

DOI: 10.1186/s12935-026-04329-9

Keywords: TERT promoter, β-catenin, hepatocellular carcinoma, MAPK/ERK pathway, liver cancer, telomerase, CTNNB1, oncogenic synergy, hydrodynamic tail vein injection, ERK1/2 phosphorylation, MEK1/2, cancer genetics

In a study published in the journal Molecular Diversity, Kader Sahin of Bahçeşehir University and Bandırma Onyedi Eylül University, Ajda Coker of Marmara University, and Serdar Durdağı of Bahçeşehir University describe a structure-based virtual screening campaign that combed through FDA-approved drugs in search of molecules capable of disrupting the interaction between β-catenin and T-cell factor 4, or Tcf4. This protein–protein interaction is the final, decisive step in Wnt signaling: when β-catenin accumulates in the cell nucleus and binds Tcf4, the complex switches on a battery of genes that drive tumor growth, survival, metastasis, and drug resistance. Block that binding, the logic goes, and the entire oncogenic program collapses.

The catch has always been the shape of the target. The β-catenin/Tcf4 interface sprawls across roughly 4,800 square angstroms, a vast and shallow surface with few of the deep, well-defined pockets that medicinal chemists traditionally exploit. For years, interfaces like this one were written off as undruggable. Yet structural biology has gradually revealed that even sprawling protein–protein interfaces concentrate their binding energy in a handful of so-called hot spots, short stretches of residues that contribute disproportionately to the affinity between the two partners. If a small molecule can be steered into those hot spots, the reasoning goes, it might achieve with a compact drug what would otherwise require a much larger molecule.

That is precisely the strategy the researchers pursued. Rather than screening synthetic chemical libraries filled with untested compounds, they turned to drug repurposing, focusing on medicines that have already passed safety scrutiny and are in clinical use. Repurposing offers a practical shortcut: known pharmacology, established safety profiles, and in many cases existing manufacturing and distribution infrastructure. The team first mapped the critical hot spot residues of β-catenin that engage Tcf4, then used molecular docking to position each candidate drug within the interface, asking which approved molecules could physically occupy and destabilize the contact points that hold the complex together.

The computational pipeline did not stop at docking. To separate plausible binders from artifacts, the researchers subjected the top candidates to physics-based molecular dynamics simulations, watching in atomic detail how each ligand behaved over time when bound to β-catenin. They then calculated binding free energies using the MM/GBSA method, a hybrid approach that combines molecular mechanics energies with implicit solvent models to estimate how strongly a ligand clings to its target. This layered filtering, docking followed by simulation followed by energetic scoring, is designed to weed out compounds that look good in a single static snapshot but fall apart under the thermal motion of a real cellular environment.

Three candidates emerged from the screen with stable binding to the critical hot spot residues of β-catenin, specifically asparagine 430, lysine 435, histidine 470, arginine 474, and lysine 508. They were Leucovorin, also known as folinic acid, a vitamin derivative routinely used to enhance chemotherapy; Carbenicillin, a penicillin-class antibiotic; and Ceforanide, a second-generation cephalosporin. All three are approved, well-characterized medicines, which means that if any of them proves effective against Wnt-driven cancers, the path from bench to bedside could be considerably shorter than for a brand-new chemical entity.

Computational predictions, however convincing, mean little until they are tested in living cells. The team moved their three hits into the laboratory, using HT-29 colorectal cancer cells, a widely studied cell line in which Wnt signaling is aberrantly active. The cells were treated with each compound and assessed for viability and for their ability to form colonies, a measure of long-term proliferative capacity that often correlates with tumorigenic potential. The results were striking: Carbenicillin and Ceforanide reduced cell viability and impaired colony formation, exhibiting superior anti-proliferative activity compared with the other candidates, including Leucovorin.

The convergence between the computational and experimental arms of the study is what gives the findings their weight. The two antibiotics that performed best in cell assays were the same molecules whose simulated binding poses anchored them most securely to the β-catenin hot spots. This consistency suggests that the anti-proliferative effects observed in HT-29 cells may indeed arise from disruption of the β-catenin/Tcf4 interaction, although the researchers are careful to frame the work as a proof of concept rather than a finished therapy. Further studies will be needed to confirm the mechanism directly, to characterize selectivity for cancer cells over healthy tissue, and to establish whether the compounds can achieve therapeutic concentrations in tumors.

Even so, the implications are considerable. Wnt/β-catenin signaling is implicated not only in colorectal cancer but in a broad family of malignancies, including hepatocellular carcinoma and other Wnt-driven tumors, and it also maintains cancer stem cell populations that fuel relapse and metastasis. A validated small-molecule inhibitor of the β-catenin/Tcf4 interaction would be a genuinely new class of anticancer agent, one that attacks the transcriptional engine of the tumor rather than a single downstream symptom. Prior efforts, including peptide mimetics and dedicated small molecules developed in academic labs, have struggled to reach the clinic, which makes the repurposing angle particularly attractive: these are drugs whose toxicity, metabolism, and drug interactions are already documented.

The study also offers a template for tackling other supposedly undruggable targets. By combining hot spot analysis, docking against a library of approved drugs, rigorous molecular dynamics validation, and energetic scoring, and only then moving to cell-based experiments, the researchers demonstrated a workflow that is both computationally disciplined and experimentally grounded. As the authors conclude, their findings provide compelling evidence that targeting the β-catenin/Tcf4 interaction with small molecules is feasible, and that Carbenicillin and Ceforanide may serve as promising repurposed candidates for therapeutic intervention in Wnt-driven malignancies. For patients with colorectal cancer, whose treatment options too often narrow as the disease progresses, the idea that answers might be hiding in plain sight among existing medicines is a hopeful one, and this study shows exactly how such hidden answers can be systematically found.

Subject of Research: Virtual drug repurposing to discover β-catenin/Tcf4 interaction inhibitors for colorectal cancer treatment

Article Title: Hot spot-driven discovery of β-catenin/Tcf4 interaction inhibitors via virtual drug repurposing study and experimental validation in colorectal cancer cells

Article References: Sahin, K., Coker, A., & Durdağı, S. (2026). Hot spot-driven discovery of β-catenin/Tcf4 interaction inhibitors via virtual drug repurposing study and experimental validation in colorectal cancer cells. Molecular Diversity. https://doi.org/10.1007/s11030-026-11720-1

Image Credits: AI Generated

DOI: 10.1007/s11030-026-11720-1

Keywords: β-catenin, Tcf4, Wnt signaling, colorectal cancer, drug repurposing, virtual screening, molecular docking, molecular dynamics, MM/GBSA, Carbenicillin, Ceforanide, protein-protein interaction inhibitors