bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–06–21
fifteen papers selected by
Xiao Qin, University of Oxford
  1. Spatial omics illuminates tumor heterogeneity.
  2. 3D multi-omics tumour atlases: from technology to biology and clinical translation.
  3. Guiding Principles: Current practices and considerations for benchmarking human gastrointestinal organoids.
  4. Cellular plasticity and epigenetic instability in cancer: Mechanistic insights and functional dissection with CRISPR-based epigenome editing.
  5. Pooled combinatorial screening identifies transcription factor sets that drive hematopoietic progenitor-like cell fate.
  6. The Aging Microenvironment Shapes Angiogenic Remodeling in IBD-Associated Colorectal Carcinogenesis.
  7. From mice to humans-divergent strategies for intestinal homeostasis and regeneration.
  8. A human induced pluripotent stem cell model for the holistic study of epithelial-to-mesenchymal transitions.
  9. Protocol for multiplexed transcription factor activity detection using optimized barcoded reporters and an automated computational pipeline.
  10. Metabolic reprogramming and plasticity of cancer stem cells.
  11. Epigenetic Gene Networks Governing Immune State Transitions Across the Lifespan.
  12. Balancing benefit and burden: rethinking post-polypectomy colonoscopy surveillance strategies.
  13. Beyond oncogenesis: the unexplored benefits of viruses in cancer immunity.
  14. Jaye Gardiner: Learning how the matrix around cells and tissues impacts cancers.
  15. In situ genetic modification of gut bacteria.
  1. Cell Rep Methods. 2026 Jun 19. pii: S2667-2375(26)00205-5. [Epub ahead of print] 101504
    Spatial omics illuminates tumor heterogeneity.
    Neha Srinivas, Serap Erdogmus, Gurkan Mollaoglu.
      Intratumoral heterogeneity (ITH) is the coexistence of diverse cancer cell states, genotypes, and microenvironmental niches within a single tumor and is a major driver of therapeutic resistance and disease progression. While the clinical implications of ITH are well appreciated, conventional methods and models have been limited in resolving the spatial and functional complexity underlying ITH. Recent advances in single-cell and spatial omics, high-plex imaging, and in vivo CRISPR perturbation and lineage tracing now enable unprecedented, mechanistic dissection of tumor ecosystems. These technologies are beginning to reveal how cell-cell interactions, spatial organization, and clonal evolution collectively shape tumor behavior and treatment response. We review emerging methods for spatial proteomics and transcriptomics, functional genomics, and clonal tracing and highlight how their integration is redefining the study of ITH. We also discuss current challenges, including scalability, accessibility, and multimodal data integration, and opportunities as cancer biology enters the spatial era.
    Keywords:  CP: cancer biology; CP: systems biology
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101504
  2. Nat Rev Cancer. 2026 Jun 15.
    3D multi-omics tumour atlases: from technology to biology and clinical translation.
    Miao Liu, Jorge Villazon, André Forjaz, Xiaolong Tian, Rong Fan, Siyuan Wang, Lingyan Shi, Denis Wirtz, Ashley L Kiemen.
      Human tumours consist of highly heterogeneous and interacting cell types organized within a complex 3D space, forming a dynamic ecosystem that evolves through the development of pre-malignant lesions, tumour initiation, progression, invasion and metastasis. Understanding the operational principles of tumour evolution at a holistic 3D level is critical for improving the ability to intercept and treat cancer early. Emerging technologies in spatial multi-omics and the generation of 3D tumour atlases are beginning to address this critical need. These efforts aim to capture the intricate interactions within precancerous lesions, tumours and their surrounding ecosystems over space and time. In this Review, we highlight emerging tools developed within and beyond the tumour atlas community and explore their potential in constructing comprehensive 3D tumour atlases. Such atlases have the potential to reveal novel biomarkers for risk stratification, early detection, preventive intervention, and transformative diagnostic and treatment strategies. Furthermore, a 3D tumour atlas can generate new insights into the molecular and cellular mechanisms driving human tumour evolution, paving the way for future research and innovation in cancer biology.
    DOI:  https://doi.org/10.1038/s41568-026-00940-0
  3. Cell Mol Gastroenterol Hepatol. 2026 Jun 13. pii: S2352-345X(26)00110-4. [Epub ahead of print] 101832
    Guiding Principles: Current practices and considerations for benchmarking human gastrointestinal organoids.
    Monica E Brown, Antoine R Gleizes, Qianhui Yu, Upasana Das Adhikari, Rekha Nagarajan, Prateeksha Rout, J Gray Camp, Omer H Yilmaz, Christopher J Tape, Matthew J Tyska, Michael P Verzi, Ken S Lau, Adam D Gracz.
      Since the first reports of organoids cultured from primary human small intestine and colonic epithelium in 2011, these systems have held considerable potential to accelerate our understanding of gastrointestinal (GI) biology and disease. Improvements in tissue isolation and culture conditions for primary tissue organoids, as well as the parallel development of protocols for generating organoids from pluripotent cells, have made organoid research increasingly accessible over the last 15 years. As organoids emerge as bona fide model systems, there is a growing need to understand and evaluate the accuracy and limitations of their ability to represent different aspects of GI biology, both within and across laboratories and experimental contexts. In this Guiding Principles commentary, we outline the current state of the field and challenges for benchmarking human small intestinal and colonic organoids against native GI tract biology. We outline a conceptual framework for approaching organoid benchmarking at multiple scales, review current approaches and efforts in assaying similarities between organoids and their source tissues, and discuss the "next frontiers" for validating organoids as reproducible and high-fidelity models of the human GI tract.
    Keywords:  Gastro-intestinal research; benchmarking; organoids; single-cell RNA-sequencing
    DOI:  https://doi.org/10.1016/j.jcmgh.2026.101832
  4. Cancer Lett. 2026 Jun 15. pii: S0304-3835(26)00443-X. [Epub ahead of print]656 218679
    Cellular plasticity and epigenetic instability in cancer: Mechanistic insights and functional dissection with CRISPR-based epigenome editing.
    Syeda Warisul Fatima.
      Cellular plasticity is a fundamental driver of tumor heterogeneity, cancer stemness, immune evasion, therapeutic resistance, and disease progression. In malignancies such as breast cancer and glioblastoma, tumor cells undergo reversible phenotypic transitions between proliferative, stem-like, invasive, and drug-tolerant states in response to intrinsic regulatory programs and extrinsic signals from the tumor microenvironment. These adaptive dynamics are governed by complex interactions among signaling pathways, transcriptional networks, chromatin remodeling, DNA methylation, histone modifications, non-coding RNAs, and immune-mediated microenvironmental cues. Such epigenetic instability enables stochastic and therapy-induced shifts between alternative cellular states, thereby contributing to tumor evolution, metastasis, resistance to targeted therapies, and variable responses to immunotherapy. Understanding the mechanisms that govern epigenetic plasticity remains a central challenge in cancer biology. Recent advances in CRISPR/dCas9-based epigenome editing have provided powerful experimental tools for investigating the functional consequences of locus-specific chromatin modifications without altering the underlying DNA sequence. Catalytically inactive Cas9 (dCas9) fused to epigenetic effector domains, including DNMT3A, TET1, KRAB, and p300, enables targeted modulation of gene expression programs implicated in cell-state transitions, lineage specification, and adaptive resistance. These technologies offer a versatile platform for interrogating causal relationships between chromatin states and cellular phenotypes and for modeling mechanisms of tumor adaptation. This review examines the molecular basis of epigenetic plasticity in cancer, evaluates current CRISPR-based epigenome editing strategies, and discusses their application in studying tumor heterogeneity, microenvironment-driven adaptation, immune escape, and therapy resistance. This study highlights emerging opportunities and persistent challenges associated with epigenome editing, including delivery barriers, durability of epigenetic modifications, context-dependent biological responses, and translational limitations. Collectively, these approaches provide valuable experimental frameworks for dissecting the regulatory logic of cancer cell plasticity while informing future therapeutic development.
    Keywords:  CRISPR/dCas9; Cancer stemness; Cellular plasticity; Epigenome editing; Immune evasion; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2026.218679
  5. Cell Syst. 2026 Jun 18. pii: S2405-4712(26)00126-2. [Epub ahead of print] 101644
    Pooled combinatorial screening identifies transcription factor sets that drive hematopoietic progenitor-like cell fate.
    James A Briggs, Janghwan Cho, Daniel Strebinger, Julia Joung, Tatum W Braun, Rhiannon K Macrae, Hojun Li, Feng Zhang.
      Mammalian cells can be directed toward specific fates by overexpression of transcription factors (TFs). However, discovering and optimizing which TFs in combination produce a state of interest remains challenging. Here, we develop a scalable screening platform that addresses this challenge by combining high multiplicity of infection (MOI), pooled delivery of barcoded TF open reading frames (ORFs), data augmentation, targeted cell enrichments, and single-cell transcriptomic readouts. As proof of principle, we apply the platform to optimize the generation of hematopoietic stem and progenitor-like cells (HSPCs) from human embryonic stem cells. Our data demonstrate technical performance across a range of key metrics and reveal a richly structured reprogramming fitness landscape over millions of TF combinations. In silico optimization of HSPC-similarity metrics over this landscape revealed two TF combinations that demonstrate superior potency in generating naive multipotent hematopoietic progenitors relative to gold-standard controls. This study demonstrates a powerful approach for data-driven cell fate engineering using complex combinatorial perturbations.
    Keywords:  cellular reprogramming; combinatorial screening; hematopoietic stem cells; transcription factor screening
    DOI:  https://doi.org/10.1016/j.cels.2026.101644
  6. Aging Cell. 2026 Jun;25(6): e70570
    The Aging Microenvironment Shapes Angiogenic Remodeling in IBD-Associated Colorectal Carcinogenesis.
    Ruoshu Duan, Qingyu Chen, Yuan Xu, Ye Yan, Sujing Jiang.
      Chronic intestinal inflammation establishes a pro-senescent microenvironment that fuels the stepwise evolution from inflammatory bowel disease (IBD) to colorectal cancer. Although cellular senescence initially functions as a tumor-suppressive barrier, the persistent accumulation of senescent cells can promote disease progression through the senescence-associated secretory phenotype (SASP). Key SASP mediators, including VEGF, IL-8/CXCL8, and matrix metalloproteinases (MMPs), reprogram endothelial and stromal compartments, driving aberrant neovascularization, vascular leakiness, extracellular-matrix remodeling, and tissue hypoxia that further reinforce inflammation and genomic instability. Emerging evidence also highlights marked heterogeneity among senescent epithelial, stromal, endothelial, and immune-cell populations within the inflamed intestinal mucosa, suggesting that distinct senescent subsets may differentially shape angiogenesis and malignant transformation. This review synthesizes current evidence linking inflammation-induced senescence to vascular dysfunction and the transition from IBD to colitis-associated colorectal cancer, and discusses therapeutic opportunities targeting the senescence-angiogenesis axis. By clarifying how the aging microenvironment reshapes intestinal angiogenesis, we propose a mechanistic framework for early intervention and cancer prevention in colitis-associated neoplasia.
    DOI:  https://doi.org/10.1111/acel.70570
  7. FEBS Lett. 2026 Jun 19.
    From mice to humans-divergent strategies for intestinal homeostasis and regeneration.
    Keiko Ishikawa, Shinya Sugimoto, Toshiro Sato.
      The intestinal epithelium is maintained by stem cells that balance self-renewal and differentiation to sustain homeostasis and enable regeneration after injury. Recent advances-including organoid culture, genome editing, orthotopic xenotransplantation, and somatic mutation-based analysis-have created new opportunities to investigate intestinal stem cell (ISC) dynamics in humans. These studies have revealed striking species-specific differences: whereas mouse LGR5+ ISCs divide daily and are chemo-sensitive, human colonic LGR5+ stem cells are predominantly slow-cycling and chemo-resistant. Consistent with this reduced cycling, human ISCs accumulate somatic mutations more slowly than those of mice. Across mammals, ISC proliferation rates inversely correlate with lifespan, a relationship thought to minimize mutation accumulation and reduce cancer risk, in line with Peto's paradox. Regenerative responses in both mice and humans can involve fetal-like reprogramming driven by YAP and other signaling pathways, yet the extent of species differences in intestinal regenerative capacity remains unclear. This review synthesizes current insights into ISC kinetics, injury responses, and evolutionary adaptations, highlighting the need for human-focused studies to bridge translational gaps and guide regenerative medicine strategies.
    Keywords:  LGR5+ stem cell; colonic stem cell; fetal‐like reprogramming; intestinal stem cell; organoid; regeneration; slow‐cycling stem cell; somatic mutation rate
    DOI:  https://doi.org/10.1002/1873-3468.70387
  8. Nat Methods. 2026 Jun 15.
    A human induced pluripotent stem cell model for the holistic study of epithelial-to-mesenchymal transitions.
    Caroline Hookway, Antoine Borensztejn, Leigh K Harris, Tiffany Barszczewski, Sara Carlson, Gokhan Dalgin, Suraj Mishra, Ellen M Adams, Julie C Dixon, Renske J Dupar, Jacqueline H Edmonds, Erik A Ehlers, Alexandra J Ferrante, Margaret A Fuqua, Clare R Gamlin, Philip Garrison, Janani Gopalan, Benjamin W Gregor, Maxwell J Hedayati, Victoria L Hurless, Kyle N Klein, Chantelle L Leveille, Sean L Meharry, Ricardo Mercado, Haley S Morris, Gouthamrajan Nadarajan, Nivedita Nivedita, Sandra A Oluoch, Serge E Parent, Amber Phan, Brock Roberts, Ashwin Samudre, Emmanuel E Sanchez, M Filip Sluzewski, Lev S Snyder, Derek J Thirstrup, Hannah F Thorp, John Paul Thottam, Julia R Torvi, Gaea Turman, Matheus P Viana, Lyndsay Wilhelm, Chamari S Wijesooriya, Jie Yao, Julie A Theriot, Ruwanthi N Gunawardane, Susanne M Rafelski.
      The epithelial-to-mesenchymal transition (EMT) is a widely studied cell state change, yet differences in model design and measurement approaches limit comparison across studies. Addressing this challenge requires experimental model systems and analysis frameworks that support standardization across contexts. Here, we show that human induced pluripotent stem (hiPS) cells in defined cell culture geometries, two-dimensional colonies and three-dimensional lumenoids, enable multimodal measurements of EMT dynamics within a single experimental platform. Using fixed-cell and live-cell image-based assays, we quantify changes in cell migration, EMT-related molecular markers, cell-cell junction organization and interactions with the basement membrane, a specialized form of the extracellular matrix, during EMT induced in hiPS cells. We identify cell culture geometry-dependent differences in the timing of migration onset and show that basement membrane integrity can be quantitatively linked to these differences. Together, these results establish an imaging-based framework for analysis of cell state transitions and provide accessible datasets and tools.
    DOI:  https://doi.org/10.1038/s41592-026-03096-9
  9. STAR Protoc. 2026 Jun 16. pii: S2666-1667(26)00319-9. [Epub ahead of print]7(3): 104666
    Protocol for multiplexed transcription factor activity detection using optimized barcoded reporters and an automated computational pipeline.
    Max Trauernicht, Vinícius H Franceschini-Santos, Hatice Yücel, Bas van Steensel.
      
    DOI:  https://doi.org/10.1016/j.xpro.2026.104666
  10. Front Cell Dev Biol. 2026 ;14 1807649
    Metabolic reprogramming and plasticity of cancer stem cells.
    Magdalena Kulus, Melania Marchel, Agnieszka Knopik-Skrocka, Krzysztof Data, Dominika Domagała, Weronika Bednarska, Paul Mozdziak, Bartosz Kempisty.
      Numerous studies in cancer biology have provided evidence of the remarkable plasticity of cancer stem cells (CSCs). These cells play a key role in tumor initiation, metastasis, and resistance to treatment. One of the most critical features of CSCs is the epithelial-mesenchymal transition, which underlies their phenotypic plasticity. CSCs can modify their metabolic profile through interactions with cancer-associated fibroblasts, tumor-associated macrophages, and regulatory t-cells. CSCs creates a multifaceted cancerous environment that adapts to extensive changes in the secretome, variability of metabolic substrates and extracellular matrix composition. Intercellular communication is mediated though tumor-derived exosomes, carrying damage-associated molecular patterns. These metabolic shifts allow cancer cells to survive and function evading a hostile, immunosuppressive environment. It is important to summarize and integrate current knowledge on the links between cancer cell metabolism, CSCs plasticity, epithelial-mesenchymal transition, and immune regulation by regulatory T cells.
    Keywords:  EMT; Tregs; cancer stem cells’ plasticity; metabolic reprogramming; resistance to therapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2026.1807649
  11. Immunology. 2026 Jun 19.
    Epigenetic Gene Networks Governing Immune State Transitions Across the Lifespan.
    Ola A Al-Ewaidat, Moawiah M Naffaa.
      Immune function across development, tissue repair, aging, and disease depends not only on signaling pathways but also on epigenetic architectures that determine whether coordinated transcriptional programs can be accessed and resolved. Increasing evidence indicates that epigenetic gene networks regulate the accessibility and reversibility of semi-stable immune states, shaping plastic, homeostatic, reparative, and degenerative configurations. We propose the concept of epigenetic transition windows, defined as temporally and contextually restricted intervals during which epigenetic constraints are relaxed, permitting coordinated and reversible transitions between immune states. During development, these windows are broad and support immune tolerance and adaptive plasticity. In adulthood they become spatially and temporally restricted, preserving stability while enabling conditional adaptation. With aging, they progressively narrow, contributing to chronic inflammation, impaired repair, and increased vulnerability to neurodegeneration. Conversely, pathological persistence of regulatory permissiveness may underlie immune evasion and sustained plasticity in cancer. We outline operational genomic readouts for quantifying transition windows, including chromatin accessibility variance, enhancer switching dynamics, reversibility metrics, and cross-cell coordination indices, and derive experimentally testable predictions that distinguish this model from pathway-centric or damage-centric explanations. By reframing immune dysfunction as a failure of regulated state transition rather than excessive signaling alone, this framework integrates inflammaging, trained immunity, immune resolution failure, and tumor immune escape within a unified regulatory architecture and provides a systems-level perspective on immune adaptability across the lifespan.
    Keywords:  chromatin accessibility; epigenetic regulation; immune plasticity; immune resolution; immune state transitions; immunosenescence; inflammaging; trained immunity; tumor immune evasion
    DOI:  https://doi.org/10.1111/imm.70161
  12. Lancet Gastroenterol Hepatol. 2026 Jun 19. pii: S2468-1253(26)00128-7. [Epub ahead of print]
    Balancing benefit and burden: rethinking post-polypectomy colonoscopy surveillance strategies.
    Dutch colonoscopy surveillance working group
      Post-polypectomy colonoscopy surveillance is widely implemented to reduce colorectal cancer incidence and mortality, yet increasing evidence raises concerns about whether current strategies are optimally balanced in terms of benefit, burden, and resource use. At least some individuals currently classified as being high risk for post-polypectomy colorectal cancer might actually have a low absolute risk, suggesting that surveillance might be overused in this group of patients. At the same time, colonoscopy surveillance imposes considerable burden at the patient, health-care system, and societal levels, including procedural risks, costs, and pressure on endoscopy capacity. This Viewpoint critically examines the limitations underlying current post-colonoscopy surveillance strategies, including reliance on historical data with inadequate collection of quality indicators, insufficient focus on the absolute risk of colorectal cancer, and potential misclassification of patients' risk. We argue that these limitations might have led to suboptimal allocation of surveillance intensity. We advocate for a shift towards a more comprehensive risk-stratified framework, in which surveillance decisions are guided by absolute colorectal cancer risk thresholds and could incorporate less invasive triage approaches for lower-risk individuals. Overall, we propose rethinking post-polypectomy surveillance to better align clinical practice with contemporary evidence with the goal of improving patient outcomes while minimising unnecessary interventions and health-care burden.
    DOI:  https://doi.org/10.1016/S2468-1253(26)00128-7
  13. Nat Rev Cancer. 2026 Jun 18.
    Beyond oncogenesis: the unexplored benefits of viruses in cancer immunity.
    Xin Wei Wang, Chi-Ping Day, Eugene V Koonin.
      The connections between viruses and cancer have historically been studied in the context of viral oncogenesis. For decades, tumour virology has focused on oncogenic viruses such as hepatitis B virus, hepatitis C virus, human papillomavirus, Epstein-Barr virus, human T cell leukaemia virus type 1, Kaposi sarcoma-associated herpesvirus and Merkel cell polyomavirus, elucidating their oncogenic mechanisms, which include mutagenesis, chronic inflammation and immune evasion. However, the human virome is vast and complex, and this oncogenesis-centred view has overshadowed the possibility that certain viral exposures enhance antitumour immunity. Through millions of years of coevolution with animal hosts, the virome, consisting of diverse bacteriophages and eukaryotic viruses, including endogenous retroviruses, appear to have evolved strategies for coexistence that shape immune development and potentiate host surveillance pathways capable of recognizing and eliminating cancer cells. Non-oncogenic viruses can prime innate and adaptive immune responses, mimic tumour antigens and modulate the expression of immune checkpoints, as exemplified by the association of the enterovirus and rhinovirus CE1 epitope with protective liver cancer immunity. Moreover, endogenous retroviruses, naturally occurring oncolytic viruses and microbiome-associated phages may act as allies in cancer control. This Review explores the emerging evidence for viral anticancer immunity, its underlying mechanisms, and implications for a virome-guided framework for cancer prevention including new approaches to risk assessment, immune-based therapeutics and applications in low-resource settings.
    DOI:  https://doi.org/10.1038/s41568-026-00948-6
  14. Sci Am. 2026 Jul 01. 335(1): 46
    Jaye Gardiner: Learning how the matrix around cells and tissues impacts cancers.
    Jeanna Bryner.
      
    DOI:  https://doi.org/10.1038/scientificamerican072026-oy6NURu5Rg1s3WiTKlL8v
  15. Curr Opin Microbiol. 2026 Jun 13. pii: S1369-5274(26)00060-3. [Epub ahead of print]92 102766
    In situ genetic modification of gut bacteria.
    Amandine Maire, Raphaël Laurenceau, Nathalie Rolhion, David Bikard.
      The crucial role of the gut microbiome in human health has driven a need to understand bacterial function within their complex native ecosystem. However, traditional functional genomic methods require isolating, cultivating, and modifying bacteria in vitro before their reintroduction in vivo. This process often necessitates the use of axenic animals or antibiotic treatments, creating artificial conditions that disrupt key microbial interactions and can obscure relevant phenotypes. This review highlights emerging tools for precise, in situ genetic manipulation of bacteria directly within the gut. We cover diverse technologies, including DNA delivery systems (e.g. engineered temperate phages, phagemids, and conjugative plasmids), and genetic perturbation strategies (e.g. CRISPR-Cas tools and transposons). These methods offer the opportunity to engineer unculturable microbes in their natural habitat and conduct genetic screens to investigate the role of specific genes and pathways. Finally, we explore the potential therapeutic applications of in situ microbiome editing.
    DOI:  https://doi.org/10.1016/j.mib.2026.102766
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