bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–09–07
thirteen papers selected by
Xiao Qin, University of Oxford



  1. Quant Biol. 2025 Dec;pii: e70004. [Epub ahead of print]13(4):
      Cellular plasticity enables cells to dynamically adapt to environmental changes by altering their phenotype. This plasticity plays a crucial role in tissue repair and regeneration and contributes to pathological processes such as cancer metastasis. Advances in single-cell omics have significantly advanced the study of cellular states and provided new opportunities for accurate cell classification and uncovering cellular transitions. In this perspective, we emphasize integrating chromatin accessibility data and extrinsic factors, such as microenvironmental cues, with single-cell transcriptomic data to develop holistic models for identifying plastic cell states. Additionally, coupling artificial intelligence with single-cell omics offers transformative potential to address existing challenges and fill gaps in identifying and characterizing plastic cells. We envision the development of a universal plasticity metric, a standardized metric for quantifying cellular plasticity. This metric would enable consistent measurement across diverse studies, creating a unified framework that bridges fields such as developmental biology, cancer research, and regenerative medicine. Fostering innovative approaches to identifying and analyzing cellular plasticity promises not only to deepen our understanding of cellular plasticity but also to accelerate therapeutic advancements, paving the way for novel precision medicine strategies to treat complex diseases such as cancer.
    Keywords:  cell plasticity; epigenetics; foundation models; single-cell omics
    DOI:  https://doi.org/10.1002/qub2.70004
  2. Cell Commun Signal. 2025 Aug 28. 23(1): 386
       BACKGROUND: Cancer cells within tumors exhibit a wide range of phenotypic states driven by non-genetic mechanisms, such as epithelial-to-mesenchymal transition (EMT), in addition to extensively studied genetic alterations. Conversions among cancer cell states can result in intratumoral heterogeneity which contributes to metastasis and development of drug resistance. However, mechanisms underlying the initiation and/or maintenance of such phenotypic plasticity are poorly understood. In particular, the role of intercellular communications in phenotypic plasticity remains elusive.
    METHODS: In this study, we employ a multiscale inference-based approach that integrates single-cell transcriptomic data to predict phenotypic changes and tumor population dynamics. Our computational framework combines ligand-receptor interaction inference (CellChat), transcription factor activity estimation (decoupleR), and causal signaling network reconstruction (CORNETO) to analyze single-cell RNA sequencing (scRNA-seq) data and investigate how intercellular interactions influence cancer cell phenotypes, with a particular focus on EMT-related gene programs. We further use mathematical models based on ordinary differential equations, informed by network inferences, to examine how intercellular communication shapes phenotypic dynamics at the population level from a dynamical systems perspective.
    RESULTS: Our inference approach reveals that signaling interactions between cancerous cells in small cell lung cancer (SCLC) result in the reinforcement of the phenotypic transition in single cells and the maintenance of population-level intratumoral heterogeneity. Additionally, we find a recurring signaling pattern across multiple types of cancer in which the mesenchymal-like subtypes utilize signals from other subtypes to support its new phenotype, further promoting the intratumoral heterogeneity. Our models show that inter-subtype communication both accelerates the development of heterogeneous tumor populations and confers robustness to their steady state phenotypic compositions.
    CONCLUSIONS: Our work highlights the critical role of intercellular signaling in sustaining intratumoral heterogeneity, and our approach of computational analysis of scRNA-seq data can infer inter- and intra-cellular signaling networks in a holistic manner.
    DOI:  https://doi.org/10.1186/s12964-025-02405-7
  3. bioRxiv. 2025 Aug 22. pii: 2025.08.18.670953. [Epub ahead of print]
      Macrophages are capable of eliminating cancer cells by phagocytosis, particularly in the presence of monoclonal antibody (mAb) therapies targeting tumor antigens. Paradoxically, tumor-associated macrophages are typically associated with poor patient outcome, and can promote tumor growth by secretion of immunosuppressive cytokines and growth factors. The mechanisms by which these pro-tumor macrophage states arise are poorly understood, and it is unclear how mAb-induced cancer cell phagocytosis may contribute to these states. To understand how antibody-dependent cancer cell phagocytosis (ADCP) alters macrophage state and function, we profiled gene expression and chromatin accessibility changes over time after ADCP. We observed that after ADCP, macrophages upregulate an anti-inflammatory gene regulatory program, characterized by expression of pro-angiogenic and immunosuppressive chemokine genes, and increased activity by cellular, oxidative, and lysosomal stress transcription factors. This gene regulatory program was shared among phagocytic macrophages following either ADCP or apoptotic cancer cell phagocytosis, in addition to substrate-specific pathways. Conditioned media from macrophages promoted EMT in cancer cells, but this pro-EMT macrophage phenotype was attenuated following ADCP, but not following apoptotic cancer cell phagocytosis. The phagocytic gene signature we identified in vitro is also expressed by tumor-associated macrophages across numerous cancer types in vivo . Together, this work identifies an anti-inflammatory and immunosuppressive epigenetic program in macrophages following ADCP upon mAb treatment, and expands our understanding of how phagocytosis influences macrophage heterogeneity in the tumor microenvironment.
    DOI:  https://doi.org/10.1101/2025.08.18.670953
  4. Front Cell Infect Microbiol. 2025 ;15 1641366
      Stem cells and organoids have emerged as pivotal biological tools for biologically relevant models. Together, these in vitro models realistically recapitulate structural and functional elements of the in vivo organ, allowing for studies of cellular, molecular, and genetic features that underpin various diseases that are difficult to observe in low-biomass tissues. Stem cells, and more recently organoids, have been applied in vivo as regenerative therapies. The emergence of the microbiome as an occupant throughout different body locales requires new approaches to understand the complex cellular interactions with the host tissue at each site. The success of regenerative medicine strategies and therapeutic development is intricately linked to this understanding and management of host-microbe dynamics. Interactions with the host microbiome and infections can both significantly impair tissue regeneration and compromise the function of stem cell-derived therapies. Therefore, a comprehensive understanding of how pathogens and the microbiome interact with stem cells and organoids is relevant for developing safe and effective regenerative medicine interventions. This review explores the evolving landscape of organoid technology, including a discussion on the importance of stem cell studies and considerations for organoid development that are important for use as models to study microbiome interactions. Additionally, this work describes the pivotal role of cell culture models in advancing host-microbe interaction studies in understudied low-biomass organs such as the stomach and reproductive tract. Through this assessment, we aim to shed light on the potential of these models to transform the approach to studying and managing infectious diseases within the context of regenerative medicine.
    Keywords:  host/microbe interactions; in vitro model; low-biomass microbiota; microbiome models; stem cells
    DOI:  https://doi.org/10.3389/fcimb.2025.1641366
  5. Cell Rep. 2025 Sep 02. pii: S2211-1247(25)00985-4. [Epub ahead of print]44(9): 116214
      Incorporating immune cells into organoids enables exploring previously inaccessible aspects of immune-epithelial interactions in vitro. In this review, we start by detailing how immune-organoid co-cultures can model mucosal immunity at each stage of a functional inflammatory response. We then describe how inflammatory organoid systems have informed our understanding of the features driving chronic stress and remodeling in autoimmune diseases and explore how patient-derived carcinoma organoids can be combined with tumor-relevant immune compartments for oncology research. We conclude by highlighting gaps that warrant focus. The ultimate aspiration is to develop systems where homeostatic dynamics are established, maintained, and perturbed in a fully mature differentiated state and where immune memory can be acquired to pathogenic challenges de novo. This would enable interrogation of immune processes with increased control and higher throughput for hypothesis testing, ultimately deepening our understanding of human immune biology in health and disease.
    Keywords:  CP: Immunology; CP: Stem cell research
    DOI:  https://doi.org/10.1016/j.celrep.2025.116214
  6. Nat Cell Biol. 2025 Sep 02.
      Current colorectal cancer mouse models either lack colon specificity, limiting progression towards more advanced disease, or preclude evaluation of resident stem cells as cancer origins. Here we report the identification of NOX1 and NPY1R as cell-surface markers enriched in LGR5+ stem cells predominantly within the caecum and exclusively within the middle and distal colorectum, respectively. Selective dysregulation of Wnt signalling in NOX1+ or NPY1R+ stem cells using CreERT2 mouse lines drives colon cancer initiation, predominantly within the caecum and rectum respectively, establishing these stem cell populations as important sources of colon cancer. Selective conditional activation of Wnt signalling and oncogenic Kras in combination with loss of TRP53 in these stem cell compartments resulted in the development of advanced, invasive cancers. This study establishes CreERT2 drivers as valuable tools for studying stem cell contributions to colon cancer.
    DOI:  https://doi.org/10.1038/s41556-025-01763-1
  7. Nature. 2025 Sep 03.
      
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-025-02768-4
  8. bioRxiv. 2025 Aug 30. pii: 2025.08.27.672635. [Epub ahead of print]
      Cell signaling plays a critical role in regulating cellular state, yet uncovering regulators of signaling pathways and understanding their molecular consequences remains challenging. Here, we present an iterative experimental and computational framework to identify and characterize regulators of signaling proteins, using the mTOR marker phosphorylated RPS6 (pRPS6) as a case study. We present a customized workflow that uses the 10x Flex assay to jointly profile intracellular protein levels, transcriptomes, and CRISPR perturbations in single cells. We use this to generate a "glossary" dataset of paired protein-RNA measurements across targeted perturbations, which we leverage to train a predictive model of pRPS6 levels based solely on transcriptomic data. Applying this model to a genome-wide Perturb-seq dataset enables in silico screening for pRPS6 and nominates novel regulators of mTOR signaling. Experimental validation confirms these predictions and reveals mechanistic diversity among hits, including changes in signaling output driven by anabolic activity, cellular proliferation and multiple stress pathways. Our work demonstrates how integrated experimental and computational approaches provide a scalable framework for multimodal phenotyping and discovery.
    DOI:  https://doi.org/10.1101/2025.08.27.672635
  9. Science. 2025 Sep 04. 389(6764): eadr8753
      Cell extrusion is essential for homeostatic self-renewal of the intestinal epithelium. Extrusion is thought to be triggered by crowding-induced compression of cells at the intestinal villus tip. In this study, we found instead that a local "tug-of-war" competition between contractile cells regulated extrusion in the intestinal epithelium. We combined quantitative live microscopy, optogenetic induction of tissue tension, genetic perturbation of myosin II activity, and local disruption of the basal cortex in mouse intestines and intestinal organoids. These approaches revealed that a dynamic actomyosin network generates tension throughout the intestinal villi, including the villus tip region. Mechanically weak cells unable to maintain this tension underwent extrusion. Thus, epithelial barrier integrity depends on intercellular mechanics.
    DOI:  https://doi.org/10.1126/science.adr8753
  10. Cell. 2025 Aug 26. pii: S0092-8674(25)00926-2. [Epub ahead of print]
      Understanding epithelial lineages of breast cancer and genotype-phenotype relationships requires direct measurements of the genome and transcriptome of the same single cells at scale. To achieve this, we developed wellDR-seq, a high-genomic-resolution, high-throughput method to simultaneously profile the genome and transcriptome of thousands of single cells. We profiled 33,646 single cells from 12 estrogen-receptor-positive breast cancers and identified ancestral subclones in multiple patients that showed a luminal hormone-responsive lineage, indicating a potential cell of origin. In contrast to bulk studies, wellDR-seq enabled the study of subclone-level gene-dosage relationships, which showed near-linear correlations in large chromosomal segments and extensive variation at the single-gene level. We identified dosage-sensitive and dosage-insensitive genes, including many breast cancer genes as well as sporadic copy-number aberrations in non-cancer cells. Overall, these data reveal complex relationships between copy number and gene expression in single cells, improving our understanding of breast cancer progression.
    Keywords:  DNA copy number; aneuploidy; breast cancer genomics; breast cancer progression; gene dosage effects; single-cell DNA and RNA sequencing; single-cell multiomics; single-cell sequencing; tumor evolution; wellDR-seq
    DOI:  https://doi.org/10.1016/j.cell.2025.08.012
  11. Cancer Immunol Res. 2025 Sep 04.
      Tumor-associated macrophages (TAMs) display remarkable functional heterogeneity, yet the molecular mechanisms driving their diverse phenotypes remain elusive. Using CRISPR screens in primary macrophages, we identified tumor-derived factors, including lactic acid, PGE2, and GM-CSF, as key modulators of TAM polarization. These factors interact synergistically and antagonistically to shape distinct TAM phenotypes that are highly conserved across human cancers. Mechanistically, lactic acid and PGE2 jointly induce angiogenic gene programs while suppressing GM-CSF-driven MHC-II expression at the chromatin level, creating mutually exclusive distributions of proangiogenic and MHC-II+ TAMs, which are differentially localized to specific spatial niches in the tumor microenvironment. Furthermore, we showed that shifting TAMs to an interferon-responsive phenotype, triggered by Adar inactivation, significantly promotes the infiltration of effector CD8+ T cells through specific receptor-ligand interactions. These findings uncover a conserved mechanism of TAM polarization and offer insights into therapeutic strategies for TAM reprogramming to potentiate cancer immunotherapy.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-0488
  12. Trends Cancer. 2025 Aug 28. pii: S2405-8033(25)00199-2. [Epub ahead of print]
      T cell therapy has curative potential for many cancers. Despite impressive clinical efficacy in hematological malignancies, current T cell therapy still faces challenges related to sustaining responses, antigen escape, cytotoxicity, limited accessibility, and difficulties in treating solid tumors. The advent of CRISPR (clustered regularly interspaced short palindromic repeats) technologies provides a promising solution to these challenges. CRISPR technologies have grown from merely tools for gene knockout to sophisticated tools that can engineer cells at various levels of the genome, epigenome, and transcriptome. In this review we discuss recent technological advancements and how their application to T cells has the potential to steer the next generation of cellular therapy. We highlight emerging applications and current technological limitations that future tool development aims to overcome.
    Keywords:  CRISPR-Cas; T cell receptor (TCR); chimeric antigen receptor (CAR); epigenome engineering; transcriptome engineering; tumor-infiltrating lymphocyte (TIL)
    DOI:  https://doi.org/10.1016/j.trecan.2025.08.001