bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–08–02
eighteen papers selected by
Xiao Qin, University of Oxford
  1. The basal cell state maintains pancreatic cancers by controlling an immunosuppressive circuit.
  2. Co-targeting deregulated WNT and MAPK signaling pathways limits phenotypic reprogramming of intestinal stem cell progeny in KRAS hyperactivated colorectal cancer.
  3. Genomic, epigenomic and transcriptomic regulation of cellular senescence.
  4. Live-Cell Imaging and Single-Cell Tracking to Monitor Clonal Dynamics and Fate Transitions in Human and Murine Intestinal Organoids.
  5. Developmentally constrained plasticity as a therapeutic vulnerability in cancer.
  6. Intestinal stem cells count to eight divisions to maintain cell ratios.
  7. Emerging Principles in Spatial Functional Genomics.
  8. Why machines don't speak biology: Toward native biological language models.
  9. Patient-Derived Organoid-Based CRISPR Screens in Cancer Research: Applications, Advances, and Challenges.
  10. CellTune: an integrative software for accurate cell classification in spatial proteomics.
  11. Inflammatory bowel disease and cancer-driving mutations occupy different cellular neighborhoods.
  12. Beyond static biomarkers: systems biology and AI for decoding cancer dynamics.
  13. Targeting the Epigenome in Colorectal Cancer.
  14. Mapping chemoattractant gradients in live tissues.
  15. Paired mutation calling and spatial transcriptomics identify cellular neighborhoods associated with the neoplastic outcome of mouse colitis.
  16. Decoding intercellular activities for more than 1,000 secreted proteins.
  17. Inference of secreted protein signaling activities in intercellular communication.
  18. Cancer stem cells are hyper-responsive sensors of the tumour microenvironment and regulate metastasis dynamics through YAP/TAZ.
  1. bioRxiv. 2026 Jul 14. pii: 2026.07.13.738221. [Epub ahead of print]
    The basal cell state maintains pancreatic cancers by controlling an immunosuppressive circuit.
    Anupriya Singhal, Kate Ryan, Samuel A Rose, Hannah C Styers, Jung Yun Kim, Nikhita Pasnuri, Ashlyn Moore, Jose Meza-Llamosas, Emma Chen, Josephine Adams, Ananya Nandula, Roshan Sharma, Zhuxuan Li, Tal Nawy, Yan Yan, Nuray Tezcan, Olca Basturk, Mara H Sherman, Dana Pe'er, Tuomas Tammela.
      Intra-tumoral heterogeneity is a cardinal feature of solid tumors, yet how distinct cancer cell states functionally contribute to malignant and stromal diversity in situ remains poorly understood. Using mouse models to lineage-trace or genetically ablate the two predominant cancer cell states in autochthonous pancreatic ductal adenocarcinoma (PDAC), we discover that basal cancer cells are highly plastic, whereas classical cancer cells exhibit limited plasticity. Strikingly, ablation of the basal, but not the classical, state induced rapid and durable tumor collapse, driven by loss of immunosuppressive cancer-associated fibroblasts, macrophage repolarization, and reprogramming of the tumor cytokine milieu, culminating in tumor destruction by cytotoxic lymphocytes. Knockout of a single cytokine, GM-CSF, specifically in basal cells recapitulated macrophage repolarization and lymphocyte recruitment observed upon basal state ablation and shrank tumors. These results reveal the basal cell state controls an immunosuppressive cell circuit critical for PDAC maintenance, motivating therapeutic targeting of the basal cells.
    DOI:  https://doi.org/10.64898/2026.07.13.738221
  2. Cancer Res. 2026 Jul 28.
    Co-targeting deregulated WNT and MAPK signaling pathways limits phenotypic reprogramming of intestinal stem cell progeny in KRAS hyperactivated colorectal cancer.
    Silvia Palladino, Rona Yaeger.
      In their recent paper, Moore and colleagues demonstrate that, upon KRAS hyperactivation, colorectal cancer (CRC) growth is driven by a reprogramming of Lrg5+ intestinal stem cells progeny towards the acquisition of a regenerative phenotype. They find that this phenotype is regulated by a balance between WNT-related intestinal stem cell and MAPK-related regenerative and proliferative transcriptional programs. By targeting both pathways, they are able to suppress this dynamic plasticity and achieve tumor regression in cell line and mouse models. The antagonistic relationship between these central pathways defined here provides key insight into genomic patterns of CRC and targeted therapy strategies.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-3173
  3. Nat Rev Genet. 2026 Jul 29.
    Genomic, epigenomic and transcriptomic regulation of cellular senescence.
    Rahagir Salekeen, Tra L Kieu, Paul D Robbins, Laura J Niedernhofer, Linshan Laux.
      Cellular senescence is a complex, highly regulated cell state induced by cellular damage and stress. Senescence is central to many areas of biology, with roles in tumour suppression, tissue regeneration, antiviral defence and diverse age-related pathologies. Senescence is characterized by stable cell cycle arrest, metabolic alterations, chromatin remodelling and the secretion of pro-inflammatory and tissue-modifying factors that are collectively termed the senescence-associated secretory phenotype. Recent technological advances, including new genetic models, single-cell and spatial multi-omics platforms and machine-learning approaches, promise to enable the phenotyping, tracing and manipulation of senescent cells with unprecedented precision and resolution. This Review defines our current understanding of the genetic pathways that regulate senescence induction, maintenance, propagation and heterogeneity, including the DNA damage response, non-genotoxic stress pathways, epigenetic changes and cell-cell communication. We also emphasize key challenges in distinguishing senescence from other cell fates and the need for next-generation biomarkers to capture the varied phenotypes and functions of senescent cells.
    DOI:  https://doi.org/10.1038/s41576-026-00982-y
  4. J Vis Exp. 2026 Jul 10.
    Live-Cell Imaging and Single-Cell Tracking to Monitor Clonal Dynamics and Fate Transitions in Human and Murine Intestinal Organoids.
    Xuan Zheng, Daniel Krueger, Johan H van Es, Hans Clevers.
      The intestinal epithelium undergoes rapid self-renewal through stem cell division, cell differentiation, and migration. Understanding how individual cells commit to specific fates and how clonal dynamics emerge within this tissue requires methods that capture cellular behavior in real time and at single-cell resolution. Intestinal organoids recapitulate key features of epithelial self-organization and cell-type diversity, making them a powerful system for studying these processes in a controlled setting. Here we present a protocol for long-term confocal live-cell imaging (up to 72 h) and single-cell tracking in human and murine intestinal organoids, built around two complementary reporter strategies. First, we describe the generation of mosaic organoids by combining differentially labeled cell populations, enabling single-cell resolution of membrane-localized and cytoskeletal reporters that cannot otherwise be attributed to individual cells in a dense epithelium. Second, we use cell-type-specific fate reporters (MUC2 for goblet cells and DEFA5 for Paneth cells) to monitor secretory cell type transitions in real time. The protocol covers organoid culture, mosaic organoid formation, sample preparation with strategies to minimize phototoxicity, image acquisition over several days, and semi-automated single-cell tracking using OrganoidTracker, which reconstructs cell trajectories and lineages over time. While demonstrated in intestinal organoids, this framework is readily adaptable to other epithelial organoid systems, including gastric, pancreatic, and colonic models, broadening its utility for studies of epithelial biology, homeostasis, and disease.
    DOI:  https://doi.org/10.3791/72058
  5. Neoplasia. 2026 Jul 29. pii: S1476-5586(26)00075-8. [Epub ahead of print]80 101344
    Developmentally constrained plasticity as a therapeutic vulnerability in cancer.
    Jie-Shen Xian, Yuan-Xiang Yang, Wei-Ling Li, Ming Liu, Xiao-Feng Zhang.
      Cancer cells can exploit developmental lineage programs to generate phenotypic heterogeneity under therapeutic pressure. Although a subset of resistant tumors preserves its founding lineage, receptor, or oncogenic dependency, accumulating evidence shows that others enter reversible persister states or stabilize alternative lineage programs. Here we frame malignant plasticity as developmentally constrained, not limitless: cell of origin, lineage history, injury memory, genetic gates, chromatin state, transcription-factor circuits, and tumor-ecosystem feedback help delimit and probabilistically bias which state transitions are accessible under therapy. We distinguish physiological expansion of state space during repair from premalignant permissiveness and malignant fixation, and classify resistance into three modes: lineage-maintained resistance, adaptive reversible plasticity, and fixed reprogramming through lineage switching or histological transformation. These modes should be read as diagnoses rather than rigid therapeutic silos. Prime-then-kill strategies are most defensible when a resistant state is reversible, targetable, and paired with readouts; they may also be considered as biomarker-defined add-on hypotheses in lineage-maintained or lineage-rerouted disease when an evidence-supported state or immune-visibility module is present. Conversely, tumors that retain driver, receptor, or lineage dependency should keep the preserved axis or bypass pathway as the therapeutic backbone, and fixed histological transformation often requires treatment according to the new lineage. We also discuss how single-cell and spatial multi-omics can map state-space breadth and ecosystem context and, when paired with perturbational designs, help test transition capacity and reversibility; static marker expression alone cannot establish plasticity. A resistance-mode-guided approach can sharpen therapeutic hypotheses and limit overgeneralization across tumor types.
    Keywords:  Cancer plasticity; Cell of origin; Developmental constraint; Drug-tolerant persisters; Lineage switching; Therapeutic resistance
    DOI:  https://doi.org/10.1016/j.neo.2026.101344
  6. Nature. 2026 Jul 29.
    Intestinal stem cells count to eight divisions to maintain cell ratios.
    Joaquín de Navascués.
      
    Keywords:  Cell biology; Epigenetics; Molecular biology; Stem cells
    DOI:  https://doi.org/10.1038/d41586-026-02128-w
  7. Curr Opin Immunol. 2026 Jul 30. pii: S0952-7915(26)00091-9. [Epub ahead of print]102 102814
    Emerging Principles in Spatial Functional Genomics.
    Alexander Tepper, Trung Nguyen, Chiara Falcomatà, Brian D Brown.
      Spatial transcriptomic and proteomic atlases have enabled mapping of gene programs within intact tissues, but these measurements remain largely descriptive and do not define the mechanisms controlling tissue biology. Pooled CRISPR screening provides scalable causal interrogation of gene function but remains largely confined to dissociated systems that lack spatial context. In vivo spatial functional genomics (SFG) bridges these approaches by integrating genetic perturbations with in situ transcriptomic and proteomic readouts to measure gene function within intact tissue ecosystems. By preserving spatial organization, SFG enables interpretation of perturbations through effects on cell-cell interactions, diffusible signals, multicellular niches, and tissue architecture. Here, we outline key design axes of SFG: perturbation strategy, barcoding strategy, and phenotypic readout. We discuss computational challenges, including spatial autocorrelation, neighborhood dependence, and context-aware null modeling, and highlight how SFG reveals non-cell-autonomous, architecture-dependent mechanisms of gene function, advancing toward predictive models of tissue organization and gene function.
    DOI:  https://doi.org/10.1016/j.coi.2026.102814
  8. Cell. 2026 Jul 28. pii: S0092-8674(26)00801-9. [Epub ahead of print]
    Why machines don't speak biology: Toward native biological language models.
    Yonatan Stelzer, Amos Tanay.
      Recent advances in AI inspire visions of universal models of biology. Yet living systems are evolved, emergent processes whose behaviors cannot be inferred from their parts alone. We propose grounding AI in canonical biological processes, constructing data-driven world models with explicit mechanistic links across molecules, cells, and their dynamics in space and time.
    Keywords:  artificial intelligence; biological computation; canonical biological processes; developmental biology; embryogenesis; emergence; evolutionary contingency; explanatory reductionism; large language models; multi-scale modeling; systems biology; world models
    DOI:  https://doi.org/10.1016/j.cell.2026.07.003
  9. Cancer Med. 2026 Aug;15(8): e72112
    Patient-Derived Organoid-Based CRISPR Screens in Cancer Research: Applications, Advances, and Challenges.
    Julianne du Plessis, Aadilah Omar.
      Patient-derived organoids (PDOs) have emerged as physiologically relevant cancer models that preserve key genetic, histological, and functional features of the tumors from which they are derived. In parallel, CRISPR-based perturbation technologies have transformed functional genomics by enabling scalable interrogation of gene function. Their integration provides a powerful framework for identifying cancer dependencies, modeling oncogenic evolution, and investigating mechanisms of drug response and resistance in patient-relevant settings. This review examines how CRISPR knockout, CRISPR interference/activation, and precision editing approaches have been applied in PDO systems to uncover context-specific vulnerabilities, reconstruct mutational trajectories, and study tumor heterogeneity. We further compare pooled and arrayed screening formats and discuss what is uniquely enabled by performing CRISPR screens in organoids rather than conventional 2D models. Particular emphasis is placed on the technical and analytical constraints of organoid-based screening, including variable editing efficiency, clonal bottlenecks, biological heterogeneity, and limited scalability. We argue that the major value of organoid-based CRISPR screening lies in its ability to identify functionally actionable cancer vulnerabilities in a patient-contextualized model, while also introducing methodological challenges that must be addressed for robust clinical translation.
    Keywords:  CRISPR screening; cancer functional genomics; drug resistance; patient‐derived organoids; precision oncology; synthetic lethality
    DOI:  https://doi.org/10.1002/cam4.72112
  10. Nat Methods. 2026 Jul 31.
    CellTune: an integrative software for accurate cell classification in spatial proteomics.
    Yuval Bussi, Dana Shainshein, Eli Ovits, Sarah Posner, Nofar Azulay, Noa Maimon, Tal Keidar Haran, Raz Ben-Uri, Caitlin Brown, Noam Schuldiner, Eylon Yaniv, David Van Valen, Idan Milo, Ofer Elhanani, Robert Schiemann, Leeat Keren.
      Spatial proteomics measures multiple proteins in situ, capturing tissue complexity. However, cell classification in densely packed tissues remains challenging because of the lack of efficient classification algorithms, annotation tools and high-quality labeled datasets to benchmark computational methods. We introduce CellTune, an integrated software for analysis of large spatial proteomics datasets, which streamlines precise cell classification through an optimized human-in-the-loop active learning workflow. It advances core capabilities for analysis of large datasets with an intuitive and code-free interface. To evaluate CellTune, we created CellTuneDepot, a resource of 40,000 manually annotated cells and 3.5 million high-quality labeled cells across 60 cell types. CellTune outperforms alternative methods, achieving accuracy comparable to human performance while enabling increased classification resolution and discovery of novel cell types. Together, CellTune and CellTuneDepot provide researchers with a tool for state-of-the-art classification accuracy and resolution at scale to drive biological insights.
    DOI:  https://doi.org/10.1038/s41592-026-03162-2
  11. Nat Genet. 2026 Jul 29.
    Inflammatory bowel disease and cancer-driving mutations occupy different cellular neighborhoods.
      
    DOI:  https://doi.org/10.1038/s41588-026-02686-9
  12. Front Syst Biol. 2026 ;6 1855016
    Beyond static biomarkers: systems biology and AI for decoding cancer dynamics.
    Subhajit Dutta, Anjana Goli.
      Precision oncology has been built largely on static biomarkers, including mutational profiles, receptor status, histopathologic classes, and single-time-point molecular signatures. These readouts have transformed diagnosis and treatment selection, but they remain mismatched to a disease whose most consequential behaviors-progression, metastasis, treatment adaptation, dormancy, and relapse-are dynamic, noisy, and multiscale. In this article, we argue that cancer is better understood as a stochastic, coupled biological system than as a fixed molecular identity. We bring together adjacent literatures spanning cancer cell states, spatial and ecological organization, metabolism and dormancy, mechanobiology, longitudinal biomarkers, quantitative oncology, and AI-enabled representation learning, and develop a mathematically grounded framework for reasoning about cancer dynamics. Our central claim is modest but consequential: future biomarkers should not only classify current disease state, but also estimate transition risk, system instability, and trajectory direction. To support that claim, we distinguish latent biological state from clinical observation, clarify why partial observability makes dynamic inference difficult, and introduce a mathematically explicit but deliberately constrained formal scaffold based on stochastic state-space models, local linearization, and layer-specific dynamical motifs. We then develop six internal biological layers of cancer dynamics-molecular regulatory dynamics, cellular state plasticity, spatial niche organization, tumor ecosystem co-evolution, metabolic-epigenetic coupling with dormancy, and mechanobiological feedback-and treat longitudinal clinical monitoring as a linked observation layer rather than a mechanistic subsystem. Particular attention is given to noise; transcriptional noise, ecological variability, treatment-induced perturbation, and measurement noise all shape how cancer states are occupied, destabilized, and detected. Finally, we review dynamic biomarker evidence from ctDNA-guided adjuvant therapy, circulating tumor cells, serial imaging, and adaptive therapy, discuss how AI can support inference under partial observability without replacing mechanism, examine regulatory and health-equity constraints, and outline the research agenda needed to turn dynamic oncology from a compelling idea into a reproducible clinical discipline.
    Keywords:  adaptive therapy; artificial intelligence; cancer dynamics; cell states; dynamic biomarkers; liquid biopsy; machine learning; mathematical oncology
    DOI:  https://doi.org/10.3389/fsysb.2026.1855016
  13. Int J Mol Sci. 2026 Jul 21. pii: 6486. [Epub ahead of print]27(14):
    Targeting the Epigenome in Colorectal Cancer.
    Antonios N Gargalionis, Kostas A Papavassiliou, Athanasios G Papavassiliou.
      Epigenetic alterations promote colorectal cancer (CRC) development, plasticity, and drug resistance. Agents have been developed to target epigenetic modifiers; however, they demonstrate limited clinical efficacy. This outcome is the result of the complex interplay within the epigenome, as well as that of the molecular circuits linking these epigenetic vulnerabilities with genetic mutations, oncogenic pathways, and activation of transcription factors. Therefore, current evidence suggests these agents should be assessed in combination with regimens including additional epigenetic drugs, immune checkpoint inhibitors, monoclonal antibodies, and chemotherapeutic drugs. Herein, we highlight recent advances towards epigenome-centered treatment strategies in CRC. We also prioritize potential efforts of epigenetic-associated therapeutic modalities, which should be further developed following integration of respective biomarkers and as tools of therapeutic reprogramming in context-dependent cellular states.
    Keywords:  DNA methylation; colorectal cancer; drug resistance; epigenetic reprogramming; epigenetic therapy; histone modifications; immunotherapy sensitization
    DOI:  https://doi.org/10.3390/ijms27146486
  14. Curr Opin Cell Biol. 2026 Jul 29. pii: S0955-0674(26)00064-5. [Epub ahead of print]102 102676
    Mapping chemoattractant gradients in live tissues.
    Boldizsár Vámosi, Balázs Enyedi.
      Chemoattractant gradients guide cell migration in immunity, tissue repair, and development, yet their spatial and temporal distribution remains difficult to measure. In this review, we discuss how the field is moving beyond static source maps and indirect cellular proxies toward direct visualization of extracellular guidance cues. We outline the strengths and limitations of classical approaches for inferring chemoattractant gradients and highlight new strategies provided by genetically encoded chemoattractant indicators (GECHIs). Emerging PBP- and GPCR-based biosensors enable continuous visualization and localization of extracellular ligands in living tissues using fluorescence intensity- or lifetime-based readouts. Although the current toolbox is limited to a small number of chemoattractants, ongoing sensor development is likely to expand ligand coverage and enable multiplexed measurements with spectrally distinct sensors in the near future.
    DOI:  https://doi.org/10.1016/j.ceb.2026.102676
  15. Nat Genet. 2026 Jul 28.
    Paired mutation calling and spatial transcriptomics identify cellular neighborhoods associated with the neoplastic outcome of mouse colitis.
    Elisa B Moutin, Linus L H Chang, Giada Giavara, Shenay Mehmed, Mathilde Colombé, Carla Boquetale, Kate Marks, Filipe C Lourenço, Nefeli Skoufou-Papoutsaki, Richard Kemp, Philippe Gascard, Thea D Tlsty, David S Tourigny, Douglas J Winton.
      In the progression from inflammatory bowel disease to associated cancer, the clonal mutational landscape shifts from selection of mutations in inflammatory genes to selection for cancer-driver mutations. How prevalence and expansion of either type of mutant clones could be impacted by the cellular environments in which they arise and how this affects the neoplastic outcome of colitis remains unknown. Here we combine in vivo lineage tracing, in silico modeling, mutational profiling and spatial transcriptomics in a mouse model of colitis-associated tumorigenesis to capture clone fates associated with chronic inflammation. We identify epithelial- and immune-enriched neighborhoods and propose a model in which establishment of a reparative tissue environment facilitates tumor initiation by promoting the selection and expansion of pro-oncogenic clones, reducing the span of inflammation-resistant neighborhoods containing nononcogenic clones.
    DOI:  https://doi.org/10.1038/s41588-026-02673-0
  16. Nat Methods. 2026 Jul 30.
    Decoding intercellular activities for more than 1,000 secreted proteins.
      
    DOI:  https://doi.org/10.1038/s41592-026-03185-9
  17. Nat Methods. 2026 Jul 30.
    Inference of secreted protein signaling activities in intercellular communication.
    Beibei Ru, Lanqi Gong, Emily Yang, Seongyong Park, George Zaki, Kenneth Aldape, Lalage Wakefield, Peng Jiang.
      The human genome encodes ~1,900 secreted proteins, many of which mediate intercellular communication. Secreted proteins do not act cell-autonomously, limiting systematic approaches to characterize their functions. Here we introduce SecAct (Secreted Activity, https://secact.ccr.cancer.gov ), a computational framework that infers the signaling activities of 1,170 human secreted proteins from spatial, single-cell and bulk transcriptomic data. The inference model harnesses precomputed intercellular signaling signatures trained on 1,258 spatial transcriptomics samples spanning 37 cancer types. Transcriptomics data from antisecreted protein therapies validate SecAct's accuracy in predicting the repression of secreted protein activity following treatment. For spatial and single-cell transcriptomics data, SecAct provides interactive modules for analyzing secreted protein-mediated cell-cell communication. Applying SecAct to 54 cancer immunotherapy cohorts comprising 5,174 patients, we identified secreted proteins associated with tumor immunity. In vivo experiments validated lymphocyte antigen 86 (LY86), whose function in cancer was previously unknown, as an antitumor regulator.
    DOI:  https://doi.org/10.1038/s41592-026-03172-0
  18. Nat Cell Biol. 2026 Jul 27.
    Cancer stem cells are hyper-responsive sensors of the tumour microenvironment and regulate metastasis dynamics through YAP/TAZ.
    Binwu Tang, Jacob Minin, Victoria M Gonzalez, Zoya Z Khan, Andrew R Gaines, Yuval Raviv, Yu-An Yang, Christine P Carney, Zachary G Millman, Daniel Grun, Cristiana M Pineda, Alina Sharma, Dominic Esposito, Hualong Yan, Jing Huang, Andy D Tran, Michael Kruhlak, Howard H Yang, Maxwell P Lee, Lalage M Wakefield.
      Cancer stem cells (CSCs) drive metastasis and therapy resistance, yet their behaviour within the complex tumour microenvironment remains poorly understood. Here we use a fluorescent reporter that marks CSCs to show that CSCs and their more differentiated progeny display strikingly different population dynamics during metastatic lung colonization in breast cancer models. CSC expansion is rapidly curtailed early in colonization, suggesting a strong negative feedback mechanism acting selectively on this subpopulation. We showed that CSCs are exceptionally sensitive to local microenvironmental cues such as cell crowding and nutrient availability. They respond earlier and more extensively than their differentiated progeny, thereby coupling tumour growth to resource and space availability. Microenvironmental signals converge on the transcriptional regulatory complex YAP/TAZ/TEAD, with CSC sensitivity arising from elevated signal reception and greater chromatin accessibility at TEAD-regulated enhancers. Targeting upstream inputs to this pathway reversed chemotherapy-induced CSC enrichment in lung metastases, suggesting a potential therapeutic strategy.
    DOI:  https://doi.org/10.1038/s41556-026-02013-8
This page is being maintained by Thomas Krichel. It was last updated on 2026‒08‒03 at 10:27.