bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–06–28
fifteen papers selected by
Xiao Qin, University of Oxford
  1. Lineage plasticity driven by GATA6 loss fuels colorectal cancer metastasis.
  2. Cancer Stem Cells as Dynamic Attractor States: Systems Biology of Tumor Plasticity and Therapy Resistance.
  3. Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts.
  4. Mapping and engineering the human cell-cell interactome.
  5. Multicellular ecosystems: Linking cellular diversity to tissue function and disease.
  6. How to give a bad talk.
  7. Dynamics and master transcription factors dependence of intestinal super-enhancers during differentiation and oncogenesis.
  8. Biological aging and generational shifts in early-onset cancer risk.
  9. A modeller's guide for biomedical discovery.
  10. Quantitative cytokine profiling of primary human macrophages reveals distinct single-cell modes of trained immunity.
  11. Beyond prediction: AI as a mechanistic microscope and digital twin for colorectal cancer immunotherapy.
  12. The metabolic basis of regulated cell death.
  13. Multi-omics analysis of extracellular vesicle cargo in cancer.
  14. Patient-derived organoids across cancers reveal conserved tumor heterogeneity and actionable therapeutic vulnerabilities.
  15. Decoding the complexity of intestinal immunity with spatial transcriptomics.
  1. Cell Stem Cell. 2026 Jun 22. pii: S1934-5909(26)00205-5. [Epub ahead of print]
    Lineage plasticity driven by GATA6 loss fuels colorectal cancer metastasis.
    Saori Goto, Vikram Deshpande, Ömer H Yilmaz, Norihiro Goto.
      Colorectal cancer (CRC) liver metastases are the leading cause of CRC-related mortality, yet the genetic and epigenetic drivers underlying this process remain poorly understood. Here, we established a pro-metastatic CRC organoid library through serial orthotopic transplantation of liver metastasis-derived organoids. Integrative RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analyses identified a pro-metastatic signature characterized by multilineage plasticity, including fetal-like and basal-like/squamous transcriptional programs. Motif and transcription factor activity analyses identified GATA6 as a key regulator of these epigenetic alterations. GATA6 expression is downregulated in liver metastases, and its genetic ablation enhances liver metastasis with minimal effects on primary tumor growth. Mechanistically, GATA6 loss triggers pro-metastatic transcriptional programs, including fetal-like and basal-like/squamous states, accompanied by LGR5- cell generation. This reprogramming is mediated by the direct repression of HNF4A and increased H3K27ac and occurs independently of SOX17. Together, these findings identify GATA6 loss as a central regulator of multilineage plasticity that drives liver metastasis in CRC.
    Keywords:  colorectal cancer; metastasis; organoid
    DOI:  https://doi.org/10.1016/j.stem.2026.05.013
  2. Stem Cells Dev. 2026 Jun 23. 15473287261458681
    Cancer Stem Cells as Dynamic Attractor States: Systems Biology of Tumor Plasticity and Therapy Resistance.
    Mahendra Aryal.
      The cancer stem cell (CSC) paradigm has evolved from a rigid hierarchical model to a systems-level perspective in which stemness is a reversible and context-dependent phenotype. Evidence from lineage tracing and single-cell/spatial multiomics indicates that tumor cells occupy continuously evolving phenotypic states governed by complex gene regulatory networks. Within this landscape, CSCs can be interpreted as metastable attractors maintained through coupled signaling, epigenetic, metabolic, transcriptional, and microenvironmental interactions. Tumor heterogeneity and therapeutic resistance emerge through phenotypic reprogramming, regulatory network rewiring, and niche-dependent stabilization under environmental and therapeutic stress. This reframes resistance as an emergent property of tumor ecosystems, underscoring the limitations of targeting static CSC populations or single pathways. Therefore, durable therapeutic control will require network-oriented interventions capable of reshaping attractor topology and disrupting stemness-supportive microenvironments.
    Keywords:  attractor states; cancer stem cells; gene regulatory networks; systems biology; therapy resistance; tumor plasticity
    DOI:  https://doi.org/10.1177/15473287261458681
  3. Cancer Cell. 2026 Jun 25. pii: S1535-6108(26)00288-6. [Epub ahead of print]
    Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts.
    Yunhe Liu, Xiongfeng Chen, Yibo Dai, Yiyue Jia, Yann Kieffer, Luyu Xie, Zhuan Zhou, Lauren Tyler, Alex C Kim, Giulia Biffi, Akshay T Krishnamurty, Fatima Mechta-Grigoriou, Ruth Scherz-Shouval, Mara H Sherman, Shannon J Turley, Linghua Wang, Huocong Huang.
      Cancer-associated fibroblasts (CAFs) form a dynamic ecosystem that critically influences tumor progression and therapeutic response. Although recent advances in single-cell and spatial omics have uncovered profound stromal diversity, interpreting the mechanistic relevance of this complexity remains a challenge. Here, we propose a more unifying conceptual framework to bridge high-dimensional data with experimental biology. By categorizing CAFs into conserved molecular phenotypes and distinct spatial archetypes, this model illustrates how CAF identities are intimately linked to local tissue contexts. This refined framework brings the complexity of the tumor stroma into greater focus, underscoring the necessary transition from broad stromal targeting toward precision, context-specific modulation. Ultimately, we hope this integrated effort will aid in the collaborative development of next-generation therapies that selectively target pathogenic stroma in cancer to improve patient outcomes.
    Keywords:  cancer-associated fibroblasts; stroma; stroma-targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2026.06.001
  4. Nat Biotechnol. 2026 Jun 23.
    Mapping and engineering the human cell-cell interactome.
    Dino Di Carlo, Leonardo Morsut, Megan L McCain, Heather J Wright, Mohamad Abedi, Sean A Yamada-Hunter, Jason Z Zhang, Keriann Backus, Eunji Chung, Yingxiao Wang, Thomas A Rando, Long Cai, Matt Thomson, Michael B Elowitz, John K Lee, Owen Witte.
      Efforts to systematically understand how cell interactions tune tissue-level function have motivated transformative advances in single-cell transcriptomics and spatial profiling. Although these technologies can measure molecular states in individual cells and their spatial mapping within tissues, they also reveal that there exists a fundamental knowledge gap of how cells influence each other in context. In this Perspective, we propose an initiative to map and engineer the human cell-cell interactome: a functional atlas of how all major human cell types communicate. We highlight how recent innovations can make this vision achievable. As a first moonshot, we propose the 'Billion Cell×Cell Project', which systematically characterizes the outcomes of defined cell-cell dyads across diverse cell types and conditions. We envision this multistage initiative will produce progressively deeper insights and unlock additional avenues for therapeutic discovery. We call on the scientific community to join us in building the tools, datasets and models that will decode and rewrite the language of life between cells.
    DOI:  https://doi.org/10.1038/s41587-026-03177-2
  5. Trends Cell Biol. 2026 Jun 24. pii: S0962-8924(26)00104-2. [Epub ahead of print]
    Multicellular ecosystems: Linking cellular diversity to tissue function and disease.
    Qiang Shi, Fei Tang, Yihan Chen, Zemin Zhang.
      Tissue function emerges from coordinated interactions among diverse cell populations, whereas disruption of these interactions can lead to dysfunction. Recent advances in single-cell and spatial genomics have not only cataloged cellular diversity but also revealed how tissues are organized as dynamic multicellular ecosystems. Moving beyond descriptive cell atlases toward functional, system-level representations represents a major frontier in tissue biology. In this review, we outline conceptual and methodological frameworks for dissecting multicellular coordination, highlight recurrent multicellular ecosystems across physiological and pathological contexts, and explore translational opportunities such as patient stratification, therapeutic reprogramming, and regenerative strategies. Viewing tissues through an ecosystem lens provides a unifying framework that links cellular diversity to emergent tissue function and informs strategies for disease intervention.
    Keywords:  cellular census; computational frameworks; multicellular coordination; single-cell and spatial genomics; translational systems medicine
    DOI:  https://doi.org/10.1016/j.tcb.2026.06.005
  6. Nat Rev Cancer. 2026 Jun 24.
    How to give a bad talk.
    Itai Yanai.
      
    DOI:  https://doi.org/10.1038/s41568-026-00954-8
  7. Nucleic Acids Res. 2026 Jun 22. pii: gkag634. [Epub ahead of print]54(12):
    Dynamics and master transcription factors dependence of intestinal super-enhancers during differentiation and oncogenesis.
    Wenxin Fang, Shuya Huang, Ruoxuan Xiao, Guangling Wei, Mingyang Zhang, Xia Qiu, Li Zou, Michael P Verzi, Yan Wang, Lei Chen.
      The intestinal epithelium is a highly regenerative tissue organized along the crypt-villus axis, where spatially compartmentalized gene expression governs stem cell renewal, proliferation, and differentiation. Super-enhancers (SEs) are large clusters of regulatory elements densely bound by transcription factors (TFs) and cofactors that drive high-level expression of genes controlling cell identity and fate, yet their roles in intestinal epithelial identity and differentiation remain unclear. Here, we generate a spatiotemporal map of SEs in the small intestine, identifying compartment-specific SEs that define crypt and villus programs. Using mouse genetic models, we identify CDX2, HNF4, and SMAD4 as core TFs orchestrating SE-driven transcriptional networks essential for epithelial differentiation. CDX2 is required for SE integrity, and its loss causes widespread SE collapse and silencing of intestinal identity genes. We further demonstrate SE remodeling during colorectal cancer, in which HNF4 and SMAD4 function as SE-associated tumor suppressors that restrain oncogenic enhancer programs. Together, our findings establish SEs as central regulators of intestinal architecture, epithelial fidelity, and tumor progression.
    DOI:  https://doi.org/10.1093/nar/gkag634
  8. Nat Med. 2026 Jun 22.
    Biological aging and generational shifts in early-onset cancer risk.
    Ruiyi Tian, Xiaoyu Zong, Duo Ren, Stefani Tica, Daniel Hong, Oluseye Oduyale, Jason D Buenrostro, Ramaswamy Govindan, Yin Cao.
      Incidence of early-onset cancer is rising globally in recent generations, which underscores the need to elucidate the influence of emerging generational risk factors. Systemic and organ-specific aging reflects the cumulative impact of exposures and may provide an integrative and complementary approach to understand early-onset cancer risk. Here among 154,169 young adults from the United Kingdom Biobank, systemic aging measured by PhenoAge increased across birth cohorts, with 23% s.d. increase for those born 1965-1974 versus 1950-1954, and was associated with early-onset solid cancer risk (hazard ratio (HR)per s.d. 1.08; 95% confidence interval (CI), 1.03-1.13), driven by lung, gastrointestinal and uterine cancers, independent of genetic risks of aging and cancer. Patterns were consistent using alternative systemic aging measures, including the Klemera-Doubal method-defined age gap and metabolomic-based age gap. These findings were validated partially among 10,262 participants in the United States All of Us Research Program. Proteomics-based organ-specific aging analyses linked immune aging with early-onset lung cancer (HRper s.d. 1.89; CI, 1.20-2.97) and adipose tissue aging to early-onset colorectal cancer (HR 1.60; CI, 1.11-2.32). Greater age gap, reflecting more advanced biological aging relative to chronological age, may serve as a driver associated with risk of early-onset solid cancers, highlighting the importance of uncovering underlying mechanisms to guide effective prevention strategies.
    DOI:  https://doi.org/10.1038/s41591-026-04448-w
  9. Dis Model Mech. 2026 06 01. pii: dmm052807. [Epub ahead of print]19(6):
    A modeller's guide for biomedical discovery.
    Philip Greulich.
      Mathematical and computational modelling can do far more than reproduce experimental data or make predictions. When used with intent, models become instruments of discovery: they translate qualitative biological ideas into quantitative, testable hypotheses; they connect microscopic questions to macroscopic data; and, crucially, they help falsify plausible but incorrect mechanistic narratives. This Perspective explores how modelling achieves these goals. I begin by outlining why classical experimental strategies and conventional statistics sometimes fall short of addressing the mechanisms we care about. I then present a model-centred workflow for scientific discovery, using clonal lineage tracing as a running example. The second half focuses on a phenomenon that both limits and empowers model inference - universality - and explains how to turn it from a curse into an opportunity. I conclude with a concise, practical guide that distils these ideas into steps for day-to-day biomedical research.
    DOI:  https://doi.org/10.1242/dmm.052807
  10. Cell Syst. 2026 Jun 23. pii: S2405-4712(26)00130-4. [Epub ahead of print] 101648
    Quantitative cytokine profiling of primary human macrophages reveals distinct single-cell modes of trained immunity.
    Aoife O'Farrell, Zijian Niu, Arjun Raj.
      Macrophages can remember prior activation and subsequently augment their response to restimulation through trained immunity. However, it remains uncertain how trained immunity phenotypes manifest in individual cells. Here, we leverage highly quantitative single-molecule RNA imaging across 90,857 individual macrophages from 26 human donors to reveal inflammatory response dynamics in trained vs. untrained populations at single-cell resolution. Different inflammatory response genes showed distinct single-cell behavior in trained populations upon restimulation. Although training increased transcription of these response genes early after restimulation, untrained populations eventually "caught up" to the transcriptional output of trained populations, highlighting the importance of sampling timescale when interpreting transcriptional assays of training. Training did not significantly alter the relationship between the transcriptional activation of different genes within the same single cell, and any single cell appeared to be capable of training. Overall, these results revealed gene-specific single-cell transcriptional changes that generate population-wide training phenotypes in macrophages.
    Keywords:  RNA FISH; inflammatory response; innate immune memory; macrophages; single cell; trained immunity
    DOI:  https://doi.org/10.1016/j.cels.2026.101648
  11. Front Immunol. 2026 ;17 1746927
    Beyond prediction: AI as a mechanistic microscope and digital twin for colorectal cancer immunotherapy.
    Zijun Zhou, Jianping Zhou.
      Colorectal cancer (CRC) remains a major cause of cancer-related death, yet the benefits of immune checkpoint inhibitors are limited to a small subset of patients, particularly those with microsatellite instability-high or mismatch repair-deficient tumors. Most patients with microsatellite-stable disease derive little benefit, and even responsive subgroups show substantial heterogeneity and acquired resistance. These challenges highlight the need for biomarkers and therapeutic frameworks that can not only predict response, but also explain underlying biology and support dynamic treatment decisions. In this review, we propose that artificial intelligence (AI) can move beyond prediction to serve two broader roles in CRC immunotherapy: as a mechanistic microscope that reveals hidden tumor-immune interactions from multimodal data, and as a digital twin that models patient-specific therapeutic trajectories over time. We summarize recent advances in AI-based pathology, imaging, and liquid biopsy for pretreatment stratification and response monitoring, and discuss how these approaches may inform resistance mapping, adaptive trial design, and strategies to convert immunologically "cold" tumors into "hot" tumors. We further examine key translational barriers, including generalizability, interpretability, and regulatory validation. By integrating multimodal data with mechanistic modeling, AI may help shift CRC immunotherapy from population-level prediction toward dynamic, individualized precision oncology.
    Keywords:  CRC (colorectal cancer); artificial intelligence; digital twin; immunotherapy; mechanistic microscope
    DOI:  https://doi.org/10.3389/fimmu.2026.1746927
  12. Cell Metab. 2026 Jun 25. pii: S1550-4131(26)00227-5. [Epub ahead of print]
    The metabolic basis of regulated cell death.
    Jiao Liu, Jiayi Wang, Rui Kang, Guido Kroemer, Daolin Tang.
      Regulated cell death (RCD) has long been conceptualized as a genetically encoded signaling process, yet its outcome is ultimately dictated by cellular metabolism. Here, we propose that cellular metabolism functions as a gatekeeper of RCD, establishing permissive or restrictive states that determine cell fate. Bioenergetic capacity, redox balance, lipid composition, and metal availability impose metabolic constraints that bias cells toward survival or distinct death modalities. At the systems level, organelle-resolved metabolism and inter-organelle communication coordinate the spatial control of death processes. We further position RCD pathways along a metabolic continuum, ranging from energy-dependent apoptosis to chemistry-driven ferroptosis. This framework explains the plasticity of death responses and suggests that metabolic reprogramming can redirect cell fate. Targeting metabolic dependencies thus offers a strategy to control cell death in disease.
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.001
  13. Trends Cancer. 2026 Jun 25. pii: S2405-8033(26)00131-7. [Epub ahead of print]
    Multi-omics analysis of extracellular vesicle cargo in cancer.
    Areti Georgiadi, Jarne Pauwels, Katleen De Preter, Kris Gevaert.
      Extracellular vesicles (EVs) are increasingly recognized as minimally invasive sources of molecular information in cancer, carrying nucleic acids, proteins, lipids, and metabolites that reflect tumor biology. Recent advances in high-throughput sequencing and mass spectrometry have not only enabled multi-omics profiling of EV cargo but also revealed that different molecular layers capture distinct yet complementary aspects of cancer processes. This review provides a comprehensive overview of the rapidly expanding landscape of EV multi-omics, highlighting methodological constraints, the predominance of proteo-transcriptomic analyses, and the principal strategies used for multi-omics layer data integration. We outline how these developments refine biomarker discovery, expose new mechanistic insights, and emphasize the need for standardized, multi-analyte EV workflows to fully realize their clinical and translational potential.
    Keywords:  cancer; cancer biomarker; extracellular vesicles; liquid biopsy; multi-omics
    DOI:  https://doi.org/10.1016/j.trecan.2026.06.003
  14. Sci Adv. 2026 Jun 26. 12(26): eadz3351
    Patient-derived organoids across cancers reveal conserved tumor heterogeneity and actionable therapeutic vulnerabilities.
    Hui-Hsuan Kuo, Bhavneet Bhinder, Hamza N Gokozan, Kathryn Gorski, Pooja Chandra, Jyothi Manohar, Daniela Guevara, John Otilano, Jenna Moyer, Marvel Tranquille, Sarah Ackermann, Jared Capuano, Cynthia Cheung, Thomas A Caiazza, Phoebe L Reuben, Anastasia Murray Tsomides, Adriana Irizarry, Michael Sigouros, David Wilkes, Abigail King, Troy Kane, Majd Al Assaad, Wael Al Zoughbi, Kentaro Ohara, Joonghoon Auh, Peter Waltman, Florencia P Madorsky Rowdo, Enrique Podaza, Valerie Gallegos, John Nguyen, Raehash Shah, Manish Shah, Allyson Ocean, Douglas Scherr, Nasser Altorki, Melissa Frey, Ana M Molina, Lisa Newman, Vivan Bea, Eloise Chapman-Davis, Marcus D Goncalves, Ashish Saxena, Parul J Shukla, Kevin Holcomb, Rachel Simmons, Scott Tagawa, Jonathan H Zippin, Evelyn Cantillo, Rohit Chandwani, Melissa Davis, Kelly Garrett, Pashtoon M Kasi, Jennifer Marti, David Nanus, Jones T Nauseef, Elizabeth Popa, Momin T Siddiqui, Alicia Alonso, Cora N Sternberg, Bishoy M Faltas, Olivier Elemento, Juan Miguel Mosquera, Andrea Sboner, M Laura Martin.
      We developed a pan-cancer patient-derived organoid (PDO) platform comprising 220 PDOs from 191 patients across 15 cancer types to advance functional precision oncology. Comprehensive characterization demonstrated high fidelity to parent tumors, with 93% histopathology concordance, 80% median genomic concordance for driver mutations, and a 0.85 median gene expression correlation. Expression profiles remained largely stable over 10 passages, ensuring reproducibility for long-term screening. Clonality analysis showed that 85% of dominant tumor clones were preserved, with genomic concordance directly reflecting clonal similarity. Even PDOs with lower concordance retained key oncogenic drivers, validating their utility as disease models. Functional assays revealed that 58% of PDOs from patients ineligible for US Food and Drug Administration-approved poly(adenosine 5'-diphosphate-ribose) polymerase inhibitors were sensitive to talazoparib, linked to DNA damage repair alterations. Furthermore, combination screens identified agents that overcome resistance, particularly in TP53-mutant models. Our platform enables the investigation of targeted therapies and molecular drivers of drug sensitivity, providing translational insights for personalized treatment beyond current biomarker guidelines.
    DOI:  https://doi.org/10.1126/sciadv.adz3351
  15. Curr Opin Immunol. 2026 Jun 23. pii: S0952-7915(26)00083-X. [Epub ahead of print]101 102806
    Decoding the complexity of intestinal immunity with spatial transcriptomics.
    Martín Suárez-Álvarez, María A Ulloa, Eduardo J Villablanca.
      The intestine integrates nutrient digestion and absorption with immune surveillance, being continuously challenged by dietary antigens, commensal microbiota, and pathogens. Its highly regionalized structure requires the immune system to balance tolerance to food and commensal organisms with protective responses against pathogens, generating substantial heterogeneity and complexity across multiple spatial scales that make it inherently difficult to study. Conventional techniques such as flow cytometry, immunohistochemistry, and RNA-sequencing can characterize immune cell location, composition, and transcriptional state, but do not enable simultaneous and unbiased interrogation of cellular state and spatial context. Over the last decade, spatial transcriptomics has allowed researchers to unbiasedly profile gene expression in situ for the first time. In this review, we discuss the suitability of spatial transcriptomics for profiling the intestinal immune system, key discoveries made using this technology, complementary techniques, current challenges, and future opportunities for its application in gut immunology research and beyond.
    DOI:  https://doi.org/10.1016/j.coi.2026.102806
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