The biobank contains 256 organoids representing five cancer types with significant unmet medical needs: colorectal, oesophageal, pancreatic, stomach and ovarian cancers. Organoids are miniature three-dimensional cultures grown from patient tumour cells. Unlike conventional two-dimensional cell lines, in which cancer cells spread across the flat surface of a laboratory dish, organoids can reproduce important features of the original tumour’s architecture, genetic diversity and behaviour. They are not complete tumours, but they provide a more biologically realistic environment for studying how cancer cells grow and respond to treatment.

Creating the collection required a coordinated network of hospital and research centres in Birmingham, Cambridge, Glasgow, London and Southampton. Fresh tumour tissue donated by consenting patients was rapidly transported to the Sanger Institute, where researchers isolated viable cancer cells and placed them in carefully controlled culture conditions. These conditions included specialised growth factors and three-dimensional scaffolds or matrices that encourage cells to organise into structures resembling aspects of the tissue from which they originated. Establishing such cultures is technically demanding because tumour samples contain a mixture of cancer cells, immune cells, connective tissue and other normal cells, and not every sample forms a stable organoid.

To determine how faithfully the organoids represented the patients’ cancers, the researchers compared DNA sequences from the organoids with sequences from the original tumours and, where available, blood samples from the same patients. This approach allowed the team to distinguish inherited genetic variants from mutations acquired by the tumour and to monitor whether the models changed as they were maintained in the laboratory. The analysis showed that the organoids generally retained key genetic characteristics of the tumours from which they were derived, supporting their use as experimental models while also providing a way to track laboratory adaptation over time.

The researchers then applied CRISPR screening to 162 organoid models. CRISPR is a genome-editing technology that can be programmed to disrupt individual genes. In a screening experiment, thousands of cells receive different gene-targeting guides, and the population is monitored to determine which genetic disruptions prevent cells from surviving or multiplying. If cells carrying a particular guide disappear from the culture, the targeted gene may be essential under those conditions. By performing these screens across many tumour models, the team could distinguish broad cancer dependencies from vulnerabilities restricted to particular cancer types or molecular subgroups.

The screens identified thousands of dependencies. Some genes were required by many cancer models, reflecting fundamental processes such as DNA replication, protein production, cell division or energy metabolism. Others were important only in tumours carrying particular mutations or genomic changes. These selective dependencies are especially interesting for drug discovery because they may offer a route to target cancer cells while limiting damage to healthy tissues. However, a gene dependency observed in an organoid is not automatically a viable drug target; it must be validated through additional experiments, tested for safety and assessed in increasingly complex biological systems.

By integrating the CRISPR results with genomic and clinical information, the researchers identified 1,733 associations between gene dependencies and tumour features. These links included specific DNA alterations and treatment histories, helping to explain why genetically different cancers may respond differently to the same therapy. The resource also provided clues about how some tumours adapt after treatment. In several cases, organoids established from the same patient before and after therapy allowed the team to compare tumour states and identify changes associated with treatment resistance, as well as weaknesses that might be exploited by alternative approaches.

The findings do not represent an immediate new treatment for patients, and the organoids are not intended to replace clinical trials or traditional cancer models. Instead, the biobank is designed as an open research platform that can help scientists prioritise hypotheses before investing in drug development. Researchers can use the models to investigate cancer biology, test combinations of therapies, study resistance mechanisms and explore why a treatment succeeds in one molecular context but fails in another. Because the models are linked to patient data and genetic information, they may also help close the gap between laboratory discoveries and the biology of cancers observed in hospitals.

The study forms part of a broader international effort to improve next-generation cancer models. Two complementary papers published in Nature describe an expanded dependency map using genome-editing screens and the Human Cancer Models Initiative’s international collection of patient-derived models. Together, the studies point toward a more systematic era of cancer research in which experimental models are selected according to the genetic and clinical features they represent. Data from the new biobank will be made freely available through the Cell Model Passports website, while organoids are expected to be distributed through Merck and the nonprofit American Type Culture Collection, allowing laboratories worldwide to investigate cancer’s vulnerabilities with shared, better-characterised tools.

Subject of Research: Cancer gene dependencies, patient-derived tumour organoids and CRISPR screening

Article Title: A tumour-derived organoid biobank maps cancer gene dependencies

News Publication Date: 5 August 2026

Web References:
Wellcome Sanger Institute: https://www.sanger.ac.uk/
Cell Model Passports: https://cellmodelpassports.sanger.ac.uk/
Wellcome: https://wellcome.org/

References:
Herranz-Ors, C. et al. (2026), “A tumour-derived organoid biobank maps cancer gene dependencies,” Nature. DOI: 10.1038/s41586-026-10830-y
“A dependency map enhanced with next-generation 3D cancer models,” Nature. DOI: 10.1038/s41586-026-10843-7
“A compendium of next-generation patient-derived models for diverse cancers,” Nature. DOI: 10.1038/s41586-026-10806-y

Keywords: Cancer, oncology, tumour organoids, cancer biobank, CRISPR screening, gene dependencies, cancer vulnerabilities, precision medicine, treatment resistance, genomics, patient-derived models, drug discovery

A new experimental study published in The Journal of Higher Education Press reports that alternative forms of focal adhesion kinase, or FAK, may represent an important and previously underexplored vulnerability in SCLC. The research, titled “Unraveling the intricacies of small cell lung cancer: FAK splicing variants as a new feature and therapeutic vulnerability of small cell lung cancer,” examined how changes in RNA processing produce FAK protein variants with properties distinct from the canonical form of the kinase. The findings suggest that these variants may influence tumor growth, invasion, and resistance to treatment.

Alternative splicing is a molecular process that allows a single gene to generate multiple messenger RNA transcripts. By selectively including or excluding specific exons, cells can produce proteins with different domains, structures, locations, and biochemical activities. This mechanism is essential in normal tissues, but it can become distorted in cancer. Abnormal splicing may create protein isoforms that support uncontrolled proliferation, alter interactions between tumor cells and their surroundings, or weaken responses to therapy. In SCLC, however, the full range and functional importance of these splicing events remain incompletely characterized.

FAK is a non-receptor tyrosine kinase that normally transmits signals generated at focal adhesions, specialized structures connecting cells to the extracellular matrix. Through its kinase activity and interactions with signaling proteins, FAK helps regulate adhesion, cytoskeletal organization, migration, survival, and mechanical responses. In many cancers, elevated FAK activity is associated with aggressive behavior and poor clinical outcomes. The new study focused on whether alternative splicing could create FAK forms that are particularly important in SCLC, where the disease’s defining genetic alterations—near-universal loss of TP53 and RB1 function—have not directly translated into effective targeted therapies.

The investigators identified FAK splicing variants that were preferentially expressed in SCLC compared with normal lung tissue and non-small cell lung cancer. According to the study, these variants arose through alternative exon inclusion or exclusion, producing proteins with altered functional characteristics. Compared with canonical FAK, the variant proteins displayed enhanced kinase activity and distinct patterns of subcellular localization. Such differences are biologically significant because the location of a signaling protein within the cell can determine which substrates it encounters and which downstream pathways it activates.

Laboratory experiments indicated that the FAK variants promoted several malignant features of SCLC cells. Cells expressing the variants showed increased proliferation, migration, and invasion, while reducing variant expression impaired tumor-associated behavior in cell-based systems and in animal models. The reported effects were linked to activation of major signaling networks, including the PI3K/AKT, MAPK, and STAT3 pathways. These pathways regulate cell survival, metabolism, proliferation, inflammatory signaling, and resistance to stress, making their coordinated activation potentially important for the highly aggressive biology of SCLC.

The study also connected FAK splicing variants to treatment resistance. SCLC is initially sensitive to chemotherapy and radiation in many patients, but surviving tumor cells can rapidly repopulate the disease. In the experiments, cells with high levels of the FAK variants displayed reduced apoptosis after exposure to chemotherapy or radiation. Apoptosis is a programmed form of cell death that many anticancer treatments are designed to trigger. Conversely, suppressing the variants increased treatment sensitivity, suggesting that altered FAK signaling may help tumor cells survive DNA damage and other stresses imposed by standard therapies.

To test the therapeutic implications of the findings, the researchers used small-molecule FAK inhibitors. These compounds reduced the kinase activity associated with the FAK variants and increased the sensitivity of SCLC cells to chemotherapy. In preclinical models, combining FAK inhibition with conventional treatment produced synergistic effects, meaning the combined response was greater than that achieved with either intervention alone. The results provide a rationale for evaluating FAK-directed combinations in SCLC, although laboratory success does not guarantee clinical benefit. Drug exposure, toxicity, tumor heterogeneity, and the ability of cancer cells to bypass blocked pathways will all require careful assessment.

The findings raise the possibility that FAK splicing variant expression could become a biomarker for selecting patients most likely to benefit from FAK-targeted therapy. They also underscore the broader importance of examining RNA processing, rather than focusing solely on DNA mutations, when searching for cancer vulnerabilities. Several questions remain unresolved, including which splicing factors drive the production of these variants, how their expression changes during tumor progression, and whether they are linked to specific SCLC subtypes or degrees of neuroendocrine differentiation. Clinical trials will ultimately be necessary to determine whether inhibiting FAK variants can improve outcomes for patients whose disease remains one of the most difficult challenges in cancer medicine.

Subject of Research: Experimental study

Article Title: Unraveling the intricacies of small cell lung cancer: FAK splicing variants as a new feature and therapeutic vulnerability of small cell lung cancer

Web References: https://doi.org/10.1007/s11684-026-1215-1

References: DOI: 10.1007/s11684-026-1215-1

Image Credits: HIGHER EDUCATION PRESS

Keywords: Small cell lung cancer, focal adhesion kinase, FAK splicing variants, alternative splicing, cancer therapy resistance, chemotherapy, radiation, PI3K/AKT, MAPK, STAT3, targeted therapy

Meibomian gland carcinoma represents a severe form of ocular cancer characterized by rapid growth and a tendency to invade surrounding tissues aggressively. Despite its severity, the molecular drivers of MGC have remained largely enigmatic, impeding the development of effective treatments. The latest research focuses on E2F2, a member of the E2F family of transcription factors, which are critical regulators of cell cycle progression and apoptosis in normal and cancerous tissues.

The authors first established a clear disparity in E2F2 expression between normal meibomian gland tissues and MGC samples. Using tissue microarrays derived from 3 normal glands and 36 tumors, they demonstrated via immunohistochemistry that E2F2 levels are significantly diminished in carcinoma tissues compared to healthy controls. This downregulation suggests an inhibitory relationship between E2F2 loss and tumor progression, overturning previous assumptions that E2F2 might act solely as an oncogene.

Importantly, these low E2F2 levels negatively correlated with proliferative markers such as Ki-67, a protein closely tied to tumor aggressiveness, while positively associating with cell cycle inhibitors P21 and P27. Such inverse and direct correlations point to a complex regulatory network in which E2F2 functions as a tumor suppressor in the context of MGC, restraining uncontrolled cellular proliferation.

To probe E2F2’s functional role, the team employed a series of sophisticated molecular assays. In vitro experiments manipulating E2F2 expression in MGC-derived cells revealed that knockdown of E2F2 enhanced proliferation, migratory capacity, and invasiveness—hallmarks of malignancy. Conversely, overexpression reversed these aggressive phenotypes. The dual outcome underscores E2F2’s vital role in maintaining cellular homeostasis and preventing tumor spread.

Flow cytometry further elucidated the mechanisms underlying these observations. Cells with suppressed E2F2 exhibited diminished apoptosis and an altered cell cycle distribution, specifically a reduction in G0/G1 phase and an increase in S phase cells, suggesting that E2F2 loss accelerates cell cycle progression. Conversely, elevating E2F2 restored apoptotic rates and normalized cell cycle phases, indicating its crucial checkpoint function governing cell proliferation.

Delving into the epigenetic landscape, the researchers identified DNA methylation as a key factor silencing E2F2 in MGC. Treatment of tumor cells with 5-aza-2′-deoxycytidine (5-aza-2-dc), a potent DNA methylation inhibitor, dramatically upregulated E2F2 expression. This change was confirmed through methylation-specific PCR, verifying a decrease in methylation levels at the E2F2 gene locus post-treatment.

RNA sequencing analyses expanded the insight into the broader genetic changes linked with methylation inhibition. They identified a total of 87 differentially expressed genes, predominantly involved in DNA replication and cell cycle processes, which align with E2F2’s established role in regulating these functions. The majority of these genes were upregulated, reflecting a global reactivation of genes suppressed by hypermethylation in MGC.

Functionally, methylation inhibition did not act in isolation but translated to tangible phenotypic effects. Treated MGC cells displayed reduced proliferation, migration, and invasiveness, aligning with the re-expression of E2F2 and the restoration of tumor-suppressive pathways. These results underscore the potential for epigenetic therapies to complement or enhance conventional treatments for MGC.

What makes this study particularly compelling is the demonstration of how epigenetic modifications modulate a transcription factor typically associated with cell proliferation, repurposing its role in a tumor-suppressive context. The dual-hit model of reduced E2F2 due to promoter methylation creates a vulnerability that can be exploited therapeutically.

By presenting E2F2 as a central node in the malignant progression of meibomian gland carcinoma driven by aberrant methylation, this research opens the possibility for clinical interventions that restore E2F2 function. Such approaches could include DNA methylation inhibitors or gene therapy aimed at enhancing E2F2 activity, representing a tailored strategy to combat this aggressive cancer subtype.

Moreover, the study’s reliance on tissue microarray analysis, functional assays, methylation studies, and integrative RNA sequencing provides a robust, multi-layered understanding of MGC pathogenesis. This comprehensive methodology strengthens the translational potential of targeting E2F2 in clinical oncology settings.

These insights also beckon further exploration into how the E2F family members interact within the epigenomic context of ocular cancers. Given E2F2’s diverse roles in other malignancies where it has occasionally been implicated as oncogenic, the present findings emphasize the tissue- and context-specific nature of transcription factor function, necessitating precision medicine approaches.

The study’s investigators highlight the urgency of continuing research into MGC molecular drivers, as current therapeutic options remain limited and patient outcomes poor. Targeting epigenetic silencing mechanisms represents an exciting frontier that could extend beyond MGC to other cancers exhibiting similar methylation-mediated gene repression.

As E2F2 emerges as a promising biomarker and molecular target, the next phases of investigation will demand clinical trials assessing the safety and efficacy of epigenetic drugs in MGC patients. Additionally, the potential to combine demethylating agents with immunotherapy or chemotherapy may offer synergistic benefits.

In conclusion, the elucidation of E2F2’s tumor-suppressive role and its repression via DNA methylation provides a compelling rationale for new targeted therapies in meibomian gland carcinoma. This innovative research marks a significant advance in ocular oncology, pointing to a future where epigenetic modulation can improve survival and quality of life for patients afflicted by this devastating cancer.

Subject of Research: The study investigates the role of E2F transcription factor 2 (E2F2) and its epigenetic regulation in the pathogenesis and progression of meibomian gland carcinoma (MGC).

Article Title: E2F2(E2F transcription factor 2) as a potential therapeutic target in meibomian gland carcinoma: evidence from functional and epigenetic studies.

Article References:
Wang, W., Wang, H., Liu, X. et al. E2F2(E2F transcription factor 2) as a potential therapeutic target in meibomian gland carcinoma: evidence from functional and epigenetic studies. BMC Cancer 25, 880 (2025). https://doi.org/10.1186/s12885-025-13833-6

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-13833-6