bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–08–09
seventeen papers selected by
Xiao Qin, University of Oxford
  1. The price of plasticity: Losing colon identity to gain metastatic potential.
  2. A tumour-derived organoid biobank maps cancer gene dependencies.
  3. Mapping enhancer-gene regulatory interactions from single-cell data.
  4. Mapping cell fate in space and time.
  5. ZFP36L2 orchestrates stress-adaptive plasticity in regeneration and cancer.
  6. Stromal cell senescence augments haematopoietic cell fitness in clonal haematopoiesis.
  7. A compendium of next-generation patient-derived models for diverse cancers.
  8. Inference of tumor spatial habitats.
  9. CRISPR/Cas9-edited organoids as a platform for tailored research of colorectal cancer.
  10. The Impact of Screening on Colorectal Cancer Mortality.
  11. Best choice for colorectal cancer screening at the population level: fecal immunochemical test, stool DNA test, or colonoscopy.
  12. Charting intratumor heterogeneity from bench to bedside.
  13. Accelerated ageing confers early-onset cancer risk.
  14. An expanded codebook of human transcription factor DNA-binding specificity.
  15. Early-career researcher co-review, one year in.
  16. Heterotypic interfacial tension between oncogenic and wild-type populations forms the mechanical basis of tissue-specific oncogenesis in epithelia.
  17. A dependency map enhanced with next-generation 3D cancer models.
  1. Cell Stem Cell. 2026 Aug 06. pii: S1934-5909(26)00265-1. [Epub ahead of print]33(8): 1246-1248
    The price of plasticity: Losing colon identity to gain metastatic potential.
    Bianca Băloiu, Hugo J G Snippert.
      The generation of highly plastic cell states in colorectal cancer that are prone to metastatic dissemination involves complex epigenetic reprogramming, rather than new genetic traits. Goto et al.1 implement a serial orthotopic organoid transplantation framework to uncover the idea that losing Gata6, a guardian of the colonic lineage, promotes metastatic competence.
    DOI:  https://doi.org/10.1016/j.stem.2026.07.005
  2. Nature. 2026 Aug 05.
    A tumour-derived organoid biobank maps cancer gene dependencies.
    OCCAMS Consortium
      Cancer cell lines remain foundational for research and drug discovery, yet they incompletely capture tumour diversity, lack linked patient context, and have undergone adaptation to culture. Tumour organoids are three-dimensional cultures derived from patient tissue that offer a powerful complement to cell lines1. Here we derived and characterized 256 clinically annotated tumour organoids directly from colorectal, oesophageal, ovarian, pancreatic and gastric cancers as renewable, genetically stable models. Extensive characterization of each model and matched patient tumour samples included whole-genome and transcriptome sequencing, and genome-wide CRISPR-Cas9 screens across 162 organoids mapped gene dependencies. Integrative analyses revealed genomic and clinical markers of dependency across common and rare subtypes, identified organoid-specific essential genes, and revealed targetable vulnerabilities following tumour evolution in paired pre- and post-treatment samples. In colorectal cancer, functional and pharmacological interrogation of the EGFR-RAS-MAPK axis uncovered differential effects of KRAS variant alleles. This open, publicly available resource provides a systematic map of gene dependencies in patient-derived organoids, expanding the model diversity and mechanistic insight needed to advance precision oncology.
    DOI:  https://doi.org/10.1038/s41586-026-10830-y
  3. Nat Genet. 2026 Aug;58(8): 1941-1952
    Mapping enhancer-gene regulatory interactions from single-cell data.
    Maya U Sheth, Wei-Lin Qiu, X Rosa Ma, Andreas R Gschwind, Evelyn Jagoda, Anthony S Tan, James Galante, Judhajeet Ray, Dulguun Amgalan, Hjörleifur Einarsson, Bram L Gorissen, Danilo Dubocanin, Christopher S McGinnis, Jacob Huang, Glen Munson, Kayla Brand, Ansuman T Satpathy, Thouis R Jones, Lars M Steinmetz, Anshul Kundaje, Berk Ustun, Jesse M Engreitz, Robin Andersson.
      Mapping enhancers and their target genes in specific cell types is crucial for understanding gene regulation and human disease genetics. However, accurately predicting enhancer-gene regulatory interactions from single-cell datasets has been challenging. Here we introduce a family of classification models, scE2G, to predict enhancer-gene regulation. These models use features from single-cell assay for transposase-accessible chromatin with sequencing (ATAC-seq) or multiomic RNA and ATAC-seq data, and are trained on a CRISPR perturbation dataset including >10,000 evaluated element-gene pairs. We benchmark scE2G models against CRISPR perturbations, fine-mapped expression quantitative trait loci and genome-wide association study variant-gene associations and demonstrate state-of-the-art performance at prediction tasks across several cell types and categories of perturbations. We apply scE2G to build maps of enhancer-gene regulatory interactions in heterogeneous tissues and interpret noncoding variants associated with complex traits, nominating regulatory interactions linking INPP4B and IL15 to lymphocyte count. The scE2G models will enable accurate mapping of enhancer-gene regulatory interactions across thousands of human cell types.
    DOI:  https://doi.org/10.1038/s41588-026-02695-8
  4. Cell Stem Cell. 2026 Aug 06. pii: S1934-5909(26)00261-4. [Epub ahead of print]33(8): 1252-1253
    Mapping cell fate in space and time.
    Hannah Stuart, Aaron McKenna.
      Cellular development unfolds across both space and time, with lineage history influencing cellular identity and tissue organization. In this issue of Cell Stem Cell, Jia et al.1 combine CRISPR lineage recording with spatial transcriptomics to reconstruct the clonal relationships and spatial organization of cells during mouse development and cancer progression.
    DOI:  https://doi.org/10.1016/j.stem.2026.07.001
  5. Nature. 2026 Aug 05.
    ZFP36L2 orchestrates stress-adaptive plasticity in regeneration and cancer.
    Qingwen Jiang, Manisha S Raghavan, Aileen M Rodriguez, Morgan Lallo, Cyrus L Tam, Saskia Hartner, Britney Forsyth, Ahmed Mahmoud, Fabian Zincke, Huiyong Zhao, Andrew Moorman, Sasha Balkaran, Kathleen Luckett, Jura Pintar, Yevgeniy Romin, Eric Chan, Anthony Santella, Bernadette Mödl, Farheen Shah, Ilyes Baali, Michael G Kharas, Elisa de Stanchina, Nil Urganci, Jinru Shia, Dana Pe'er, Francisco Sanchez-Vega, Richard Koche, Quaid Morris, Joseph M Chan, Karuna Ganesh.
      Phenotypic plasticity is a hallmark of cancer1; however the molecular switches required for cell-fate reprogramming are poorly understood. During intestinal wound-healing and colorectal cancer (CRC) metastasis, differentiated cells can dynamically dedifferentiate into an intestinal stem cell (ISC) state to drive epithelial regeneration and metastatic outgrowth2-10. Here we show that the RNA-binding protein ZFP36L2, which is mutated in 5-10% of CRC11-15, is a pivotal stress-responsive orchestrator of dynamic dedifferentiation. In mouse colon regeneration models, ZFP36L2 ablation inhibits dedifferentiation, ISC gene expression and function and impairs intestinal regeneration. In human CRC, loss of ZFP36L2 function abrogates metastatic seeding and the outgrowth of LGR5+ canonical metastases while promoting lineage plasticity and non-canonical differentiation into heterogeneous cell states. Mechanistically, ZFP36L2 binds to stress-associated mRNAs that contain AU-rich 3' untranslated regions, which induces the formation of dynamic biomolecular condensates associated with mRNA degradation and termination of the stress response. Together, these data show that ZFP36L2 acts as an important molecular switch that couples stress sensing with phenotypic plasticity. This in turn drives cellular dedifferentiation essential for re-establishing the ISC state during wound healing and metastasis. In ZFP36L2-deficient CRC, the inability to re-enter the LGR5+ state during metastatic outgrowth promotes non-canonical lineage plasticity, which is associated with poor clinical outcomes.
    DOI:  https://doi.org/10.1038/s41586-026-10890-0
  6. Nat Cell Biol. 2026 Aug 06.
    Stromal cell senescence augments haematopoietic cell fitness in clonal haematopoiesis.
    Jayna J Mistry, Kira A Young, Anna Navarro Figueredo, Gibran Edun, Alicia G Aguilar-Navarro, Patricia A Colom Díaz, Maria Telpoukhovskaia, Inés Fernández Maestre, Sheng F Cai, Katharina S Götze, Anastasia N Tikhonova, Ross L Levine, Jennifer J Trowbridge.
      Microenvironment remodelling impacts tumour growth and metastasis, but whether remodelling promotes pre-malignant clonal fitness remains unknown. Here, using single-cell RNA-sequencing of the bone-marrow microenvironment in a mouse model of DNMT3A-mutant clonal haematopoiesis (CH), we identify mesenchymal stromal cells (MSCs) in a molecular state of cellular senescence. Elevated bone-marrow MSC senescence is also observed in humans with CH driven by several common somatic mutations. MSC senescence is induced by mutant haematopoietic cells in a contact-independent manner through production of soluble factors including TNF-α and IL-6. These cytokines activate a Stat3-driven pathway that is necessary and sufficient for MSC senescence induction. Genetic or pharmacological depletion of senescent non-haematopoietic cells reduces the burden of CH and delays progression to myeloid neoplasia. Our findings show that microenvironment remodelling modifies pre-malignant clonal fitness and identifies disruption of the crosstalk between pre-malignant cells and their niche as a cancer prevention strategy.
    DOI:  https://doi.org/10.1038/s41556-026-02025-4
  7. Nature. 2026 Aug 05.
    A compendium of next-generation patient-derived models for diverse cancers.
    HCMI Network
      The development of new therapeutics and the validation of pathogenetic cancer mechanisms require representative laboratory models1,2. However, existing collections represent only a fraction of the diversity observed in human cancer2-4. Recent technologies have enabled efficient in vitro model derivation (for example, tumour organoids)5. However, whether these maintain essential properties of patient tumours during long-term expansion has not been systematically investigated. Here we present results of a large-scale international programme-the Human Cancer Models Initiative-which involved the generation of a resource of 665 next-generation models from 2,780 donors with 25 cancer types and integrated tumour-model whole genome, exome, methylome and transcriptome analyses. The resource provides 522 models with comprehensive clinical data, 153 models of rare cancers and 71 models from participants with non-European ancestry. Analyses of 421 matched tumour-model pairs reveal high genetic (97.8%) and epigenetic (95%) concordance and define correlates of model discordance. Single-nucleus RNA sequencing of tumour-model pairs reveals subsets of models in which culture conditions significantly influence cell states. Finally, we characterize model preservation of extrachromosomal DNA and post-treatment mutational signatures to provide opportunities to study therapeutic resistance. This model repository is being made available to the community-including multimodal molecular profiling, clinical information and integrative software tools-thus providing a valuable resource for preclinical investigation of cancer pathogenesis and treatment response.
    DOI:  https://doi.org/10.1038/s41586-026-10806-y
  8. Nat Methods. 2026 Aug;23(8): 1487
    Inference of tumor spatial habitats.
    Lin Tang.
      
    DOI:  https://doi.org/10.1038/s41592-026-03192-w
  9. Neoplasma. 2026 Aug 04. pii: 260529N175. [Epub ahead of print]
    CRISPR/Cas9-edited organoids as a platform for tailored research of colorectal cancer.
    Nikoleta Mojzesova, Petra Hladikova, Zuzana Kozovska, Martina Poturnajova, Silvia Tyciakova, Miroslava Matuskova.
      Colorectal cancer is one of the most commonly diagnosed cancers worldwide. Mortality rates and limited therapeutic options justify the development of reliable preclinical research models, as their translational value remains limited. Simple in vitro models do not recapitulate tumor heterogeneity, while in vivo research faces ethical concerns and interspecies differences. Patient-derived organoids offer a physiologically more relevant platform that retains the genetic, epigenetic, and phenotypic characteristics of the original tumor. Tumor-derived organoids enable precise investigation of novel treatments, functional genomics, and modeling of cancer development. Integration with CRISPR/Cas9 gene editing further enables accurate manipulation of specific genes to study carcinogenesis and therapeutic resistance. This review highlights recent advances in the use of organoids for colorectal cancer research and explores the potential of gene-edited organoids to discover the genetic and molecular mechanisms underlying colorectal cancer development, progression, and treatment resistance.
    DOI:  https://doi.org/10.4149/neo_2026_260529N175
  10. JAMA Netw Open. 2026 Aug 03. 9(8): e2626848
    The Impact of Screening on Colorectal Cancer Mortality.
    Uri Ladabaum.
      
    DOI:  https://doi.org/10.1001/jamanetworkopen.2026.26848
  11. Clin Endosc. 2026 Jun 15.
    Best choice for colorectal cancer screening at the population level: fecal immunochemical test, stool DNA test, or colonoscopy.
    Hyoung Il Choi, Jae Myung Cha.
      Fecal immunochemical testing (FIT) remains the cornerstone of organized, population-based colorectal cancer (CRC) screening owing to its noninvasive nature, affordability, and proven mortality reduction. FIT facilitates early detection; however, its population impact depends on sustained participation, adequate colonoscopy capacity for positive results, and data-driven optimization of thresholds and intervals. Stool DNA-based tests offer higher sensitivity for CRC and advanced adenomas than FIT, with lower specificity and higher costs. Multitarget stool DNA tests may serve as complementary options within hybrid risk-stratified strategies; however, further evidence is needed regarding their long-term effectiveness, programmatic feasibility, and economic sustainability before widespread adoption at the population level. In contrast, methylation-based stool DNA tests utilize stable epigenetic alterations and simpler laboratory workflows, offering advantages in logistics, scalability, and cost-effectiveness, and thus represent promising candidates for organized screening. Colonoscopy remains the most comprehensive screening modality, enabling the detection and removal of precancerous lesions, thereby preventing the development of CRC. However, its use as an organized screening tool at the population level is limited by its invasiveness, cost, logistical complexity, and suboptimal participation, which compels most organized programs to position colonoscopy primarily as a confirmatory test following noninvasive screening rather than as a universal first-line modality.
    Keywords:  Colonoscopy; Colorectal neoplasms; DNA; Epigenesis, genetic; Methylation
    DOI:  https://doi.org/10.5946/ce.2026.061
  12. Nat Cancer. 2026 Aug 07.
    Charting intratumor heterogeneity from bench to bedside.
    Jonathan C M Wan, Nicholas McGranahan, Charles Swanton.
      Intratumor heterogeneity poses a fundamental challenge across the cancer care continuum, from diagnosis to treatment resistance and metastasis. Over recent decades, multiregion and multiomic profiling of tissue, together with functional studies and longitudinal plasma sampling, have revealed the dynamic and multidimensional evolution of tumor ecosystems. This complexity spans genetic and non-genetic mechanisms within cancer cells and their microenvironment. In this Review, we synthesize the current understanding of heterogeneity and evolution and discuss how these insights can inform the development of evolution-aware diagnostic and therapeutic strategies.
    DOI:  https://doi.org/10.1038/s43018-026-01198-z
  13. Nat Rev Cancer. 2026 Aug 03.
    Accelerated ageing confers early-onset cancer risk.
    Anna Dart.
      
    DOI:  https://doi.org/10.1038/s41568-026-00967-3
  14. Nature. 2026 Aug 05.
    An expanded codebook of human transcription factor DNA-binding specificity.
    Codebook Consortium
      Gene expression is regulated by transcription factors (TFs), which recognize specific DNA sequence motifs. Several hundred putative human TFs, identified mainly by an apparent DNA-binding domain, lack known binding motifs1. Furthermore, even for well-characterized TFs, it remains controversial the degree to which motifs accurately reflect binding sites in living cells2. Here we describe a systematic effort ('Codebook') to determine the sequence specificity of 332 putative and poorly characterized human TFs. More than 4,000 independent experiments, encompassing multiple in vitro and in vivo assays, produced motifs for just over half (177; 53%) of the TFs, of which most are associated with only a single protein. These results extend the vocabulary of sequence recognition encoded by human TFs by around 130 distinct motifs. Moreover, binding motifs identified in vitro are strongly enriched in cellular binding sites. Collectively, the data reveal tens of thousands of previously unknown, conserved and direct TF-binding sites across the human genome. These sites are concentrated in promoter regions and are predictive of gene expression. In summary, this new codebook provides an important step forward in decoding the human genome.
    DOI:  https://doi.org/10.1038/s41586-026-10798-9
  15. Nat Methods. 2026 Aug;23(8): 1471
    Early-career researcher co-review, one year in.
      
    DOI:  https://doi.org/10.1038/s41592-026-03197-5
  16. Elife. 2026 Aug 06. pii: RP106893. [Epub ahead of print]14
    Heterotypic interfacial tension between oncogenic and wild-type populations forms the mechanical basis of tissue-specific oncogenesis in epithelia.
    Amrapali Datta, Phanindra Dewan, Aswin Anto Puthoor, Tanya Chhabra, Tanishq Tejaswi, Sindhu Muthukrishnan, Akshar Rao, Sumantra Sarkar, Medhavi Vishwakarma.
      Why does the same oncogenic mutation drive tumor formation in some tissues but not in others? While cancer driver mutations are well documented, their tissue-specific effects remain largely attributed to genetic factors, leaving the biophysical aspects underexplored. Here, we demonstrate that mechanical interactions between newly transformed and wild-type cells are critical in determining survival and growth of HRasV12 mutants in human mammary and bronchial epithelia, producing contrasting outcomes in the two tissues. In mammary epithelium, isolated mutants are extruded - typical of epithelial defense against cancer - while mutant groups become spatially confined in kinetically arrested, jammed clusters, marked by an actomyosin belt at the interface. In contrast, bronchial epithelium permits persistent spreading of the mutants, which form long protrusions regardless of colony size. Furthermore, oncogenic clusters in the two tissues exhibit distinct biophysical properties, including variations in cell shapes, intracellular pressure, cell-cell tension, and cellular motility. Using a cell shape-tension coupled bi-disperse vertex model, we reveal that interfacial tension at mutant-wild-type boundaries dictates whether mutants are eliminated, restrained, or expanded. Additionally, modulating the heterotypic interfacial tension alters mutant cluster fates. Together, our findings uncover a mechanical basis for tissue-specific oncogenesis by highlighting how interfacial mechanics between mutants and wild-type populations regulate tumor initiation and progression.
    Keywords:  breast epithelial cells; cancer biology; lung epithelial cells; mammalian cells
    DOI:  https://doi.org/10.7554/eLife.106893
  17. Nature. 2026 Aug 05.
    A dependency map enhanced with next-generation 3D cancer models.
    James V Neiswender, Samuel Maffa, Lisa Brenan, Dina ElHarouni, Yejie Yun, Isabella Boyle, Kirsty Wienand, Haider Inam, Tate Bertea, Ashley Anderson, Megan Wong, Matias Enriquez, Evan Lenz, Beatriz Villafranca, Nora Shanks, Mary Hager, Nia Lloyd, Hannah Shadmany, Sarah J Wie, Harry Liang, Konnor Yunghans, Xiaomeng Zhang, Lauren Golden, Hannah Harris, Serena Day, Philip Montgomery, Samantha Stokes, Ross M Giglio, Cynthia Hajal, James R Whittle, Guadalupe Garcia, Caitlin E Mills, Mehdi Touat, Kristine Pelton, Hongyu Li, Prem Sai Prabhakar, Sonja Herter, Zoe Hoffmann Kamrat, Dan Gui, Julien Dilly, Chen Khuan Wong, Jimmy A Guo, Sangita Pal, Yossef Baidi, Ryan Johnston, Daniel D Brown, Sonam Bhatia, Peter S Winter, Srivatsan Raghavan, Rameen Beroukhim, Eva Colas, David L Spector, Adam J Bass, Peter K Sorger, Yu Chen, Sarah J Hill, Steffi Oesterreich, Adrian V Lee, Himisha Beltran, Jesse S Boehm, Yuen-Yi Tseng, David E Root, William C Hahn, Andrew J Aguirre, Catarina D Campbell, Keith L Ligon, Joshua M Dempster, Tsukasa Shibue, Francisca Vazquez.
      Despite advances in precision oncology, effective personalized treatments are still lacking for most patients with cancer1. The Cancer Dependency Map (DepMap) accelerates this field by systematically identifying cancer vulnerabilities in diverse preclinical models. Data from over 1,300 cell lines have led to the discovery of new therapeutic strategies across multiple tumour types2. However, mapping cancer vulnerabilities using traditional cell lines has limitations, including insufficient cancer subtype representation and the impact of culture conditions on perturbation responses. Here we perform 147 genome-scale CRISPR screens and multi-omic characterizations of next-generation (NextGen) cancer models (organoids and spheroids) across 10 cancer types. This strategy enables the expansion of DepMap to cover new genomic and molecular subtypes and to identify new biomarker-associated vulnerabilities. These new models also preserve transcriptional programs that are silenced in traditional cell lines and facilitate the discovery of specific gene dependencies associated with these programs. Comparisons of traditional and NextGen cancer models enable further identification of distinct effects of growth format and culture medium on gene essentiality. The integrated dataset combines data from both model types to offer a valuable, expansive resource for exploring cancer vulnerabilities and is accessible via the DepMap portal.
    DOI:  https://doi.org/10.1038/s41586-026-10843-7
This page is being maintained by Thomas Krichel. It was last updated on 2026‒08‒13 at 12:49.