bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–06–08
fourteen papers selected by
Xiao Qin, University of Oxford
  1. EYKTHYR reveals transcriptional regulators of spatial gene programs.
  2. High-definition spatial transcriptomic profiling of immune cell populations in colorectal cancer.
  3. Barcoded monoclonal embryoids are a potential solution to confounding bottlenecks in mosaic organoid screens.
  4. Engineering next-generation microfluidic technologies for single-cell phenomics.
  5. Acquired resistance in cancer: towards targeted therapeutic strategies.
  6. The plasticity of cancer-associated fibroblasts.
  7. Loss of colonic fidelity enables multilineage plasticity and metastasis.
  8. Next generation lineage tracing and its applications to unravel development.
  9. Atlas-scale metabolic activities inferred from single-cell and spatial transcriptomics.
  10. Redefining familial adenomatous polyposis: competition, cooperation, and the path to monoclonality.
  11. Lineage recording in monoclonal gastruloids reveals heritable modes of early development.
  12. A systems view of cellular heterogeneity: Unlocking the "wheel of fate".
  13. Spatial epigenomic niches underlie glioblastoma cell state plasticity.
  14. Organism-wide cellular dynamics and epigenomic remodeling in mammalian aging.
  1. bioRxiv. 2025 May 23. pii: 2025.05.19.654884. [Epub ahead of print]
    EYKTHYR reveals transcriptional regulators of spatial gene programs.
    Spencer Krieger, Ellie Haber, Jian Ma.
      Understanding how transcription factors (TFs) orchestrate gene regulatory networks that define complex tissue structures is central to uncovering tissue organization and disease mechanisms. Although spatial multiome technologies now enable in situ measurement of both transcriptional activity and chromatin accessibility, existing computational methods either overlook spatial tissue context or are hindered by the high dropout rates characteristic of such data. Here, we introduce E ykthyr , a computational framework that integrates gene expression and chromatin accessibility within a spatially aware model to identify TFs driving spatial gene programs. E ykthyr mitigates dropout effects by leveraging interpretable, low-dimensional embeddings of gene expression and chromatin accessibility - both linear with respect to their input - enabling robust identification and scalable inference of spatial transcriptional regulators. Applied across diverse spatial multiome datasets, E ykthyr consistently outperforms existing approaches, accurately identifying TFs that coordinate spatial gene programs in mouse brain development and regulate T-cell states within tumor microenvironments. E ykthyr establishes a foundation for decoding how TFs interpret local intercellular signaling to shape tissue structure, offering insights into the regulatory logic underlying spatial organization in health and disease.
    DOI:  https://doi.org/10.1101/2025.05.19.654884
  2. Nat Genet. 2025 Jun 05.
    High-definition spatial transcriptomic profiling of immune cell populations in colorectal cancer.
    Visium HD Development Team
      A comprehensive understanding of cellular behavior and response to the tumor microenvironment (TME) in colorectal cancer (CRC) remains elusive. Here, we introduce the high-definition Visium spatial transcriptomic technology (Visium HD) and investigate formalin-fixed paraffin-embedded human CRC samples (n = 5). We demonstrate the high sensitivity, single-cell-scale resolution and spatial accuracy of Visium HD, generating a highly refined whole-transcriptome spatial profile of CRC samples. We identify transcriptomically distinct macrophage subpopulations in different spatial niches with potential pro-tumor and anti-tumor functions via interactions with tumor and T cells. In situ gene expression analysis validates our findings and localizes a clonally expanded T cell population close to macrophages with anti-tumor features. Our study demonstrates the power of high-resolution spatial technologies to understand cellular interactions in the TME and paves the way for larger studies that will unravel mechanisms and biomarkers of CRC biology, improving diagnosis and disease management strategies.
    DOI:  https://doi.org/10.1038/s41588-025-02193-3
  3. bioRxiv. 2025 May 24. pii: 2025.05.23.655669. [Epub ahead of print]
    Barcoded monoclonal embryoids are a potential solution to confounding bottlenecks in mosaic organoid screens.
    Samuel G Regalado, Chengxiang Qiu, Jean-Benoît Lalanne, Beth K Martin, Madeleine Duran, Cole Trapnell, Aidan Keith, Silvia Domcke, Jay Shendure.
      Genetic screens in organoids hold tremendous promise for accelerating discoveries at the intersection of genomics and developmental biology. Embryoid bodies (EBs) are self-organizing multicellular structures that recapitulate aspects of early mammalian embryogenesis. We set out to perform a CRISPR screen perturbing all transcription factors (TFs) in murine EBs. Specifically, a library of TF-targeting guide RNAs (gRNAs) was used to generate mouse embryonic stem cells (mESCs) bearing single TF knockouts. Aggregates of these mESCs were induced to form mouse EBs, such that each resulting EB was 'mosaic' with respect to the TF perturbations represented among its constituent cells. Upon performing single cell RNA-seq (scRNA-seq) on cells derived from mosaic EBs, we found many TF perturbations exhibiting large and seemingly significant effects on the likelihood that individual cells would adopt certain fates, suggesting roles for these TFs in lineage specification. However, to our surprise, these results were not reproducible across biological replicates. Upon further investigation, we discovered cellular bottlenecks during EB differentiation that dramatically reduce clonal complexity, curtailing statistical power and confounding interpretation of mosaic screens. Towards addressing this challenge, we developed a scalable protocol in which each individual EB is monoclonally derived from a single mESC and genetically barcoded. In a proof-of-concept experiment, we show how these monoclonal EBs enable us to better quantify the consequences of TF perturbations as well as 'inter-individual' heterogeneity across EBs harboring the same genetic perturbation. Looking forward, monoclonal EBs and EB-derived organoids may be powerful tools not only for genetic screens, but also for modeling Mendelian disorders, as their underlying genetic lesions are overwhelmingly constitutional ( i.e. present in all somatic cells), yet give rise to phenotypes with incomplete penetrance and variable expressivity.
    DOI:  https://doi.org/10.1101/2025.05.23.655669
  4. Nat Genet. 2025 Jun 02.
    Engineering next-generation microfluidic technologies for single-cell phenomics.
    Camille L G Lambert, Guido van Mierlo, Johannes J Bues, Orane J Guillaume-Gentil, Bart Deplancke.
      The completion of the Human Genome Project catalyzed the development of 'omics' technologies, enabling the detailed exploration of biological systems at an unprecedented molecular scale. Microfluidics has transformed the omics toolbox by facilitating large-scale, high-throughput and highly accurate measurements of DNA and RNA, driving the transition from bulk to single-cell analyses. This transition has ushered in a new era, moving beyond a gene- and protein-centric perspective toward a holistic understanding of cellular phenotypes. This emerging 'single-cell phenomics era' integrates diverse omics datasets with spatial, morphological and temporal phenotypes to provide a comprehensive perspective on cellular function. This Review highlights how microfluidics addressed key challenges in the transition to single-cell omics and explores how lessons learned from these efforts will propel the single-cell phenomics revolution. Furthermore, we discuss emerging opportunities in which integrative single-cell phenomics could serve as a foundation for transformative discoveries in biology.
    DOI:  https://doi.org/10.1038/s41588-025-02198-y
  5. Nat Rev Cancer. 2025 Jun 03.
    Acquired resistance in cancer: towards targeted therapeutic strategies.
    National Cancer Institute (NCI) Acquired Resistance to Therapy Network (ARTNet)
      Development of acquired therapeutic resistance limits the efficacy of cancer treatments and accounts for therapeutic failure in most patients. How resistance arises, varies across cancer types and differs depending on therapeutic modalities is incompletely understood. Novel strategies that address and overcome the various and complex resistance mechanisms necessitate a deep understanding of the underlying dynamics. We are at a crucial time when innovative technologies applied to patient-relevant tumour models have the potential to bridge the gap between fundamental research into mechanisms and timing of acquired resistance and clinical applications that translate these findings into actionable strategies to extend therapy efficacy. Unprecedented spatial and time-resolved high-throughput platforms generate vast amounts of data, from which increasingly complex information can be extracted and analysed through artificial intelligence and machine learning-based approaches. This Roadmap outlines key mechanisms that underlie the acquisition of therapeutic resistance in cancer and explores diverse modelling strategies. Clinically relevant, tractable models of disease and biomarker-driven precision approaches are poised to transform the landscape of acquired therapy resistance in cancer and its clinical management. Here, we propose an integrated strategy that leverages next-generation technologies to dissect the complexities of therapy resistance, shifting the paradigm from reactive management to predictive and proactive prevention.
    DOI:  https://doi.org/10.1038/s41568-025-00824-9
  6. Trends Cancer. 2025 Jun 04. pii: S2405-8033(25)00108-6. [Epub ahead of print]
    The plasticity of cancer-associated fibroblasts.
    Zihan Xia, Olivier De Wever.
      The plasticity of cancer-associated fibroblasts (CAFs) refers to their ability to adopt a spectrum of distinct phenotypes or states in response to dynamic changes within the tumor microenvironment (TME). Recent advances in single-cell technologies have enabled detailed characterization of the heterogeneity and spatial complexity of CAF subpopulations across multiple tumor types. Notably, CAF subtypes undergo dynamic transitions during tumor progression and therapy pressure. This review systematically summarizes the current knowledge on CAF plasticity shaped by both intrinsic and extrinsic factors, delineates research gaps, and highlights CAF phenotypic switching as a potential therapeutic opportunity.
    Keywords:  cancer-associated fibroblasts; fibroblast heterogeneity; fibroblast plasticity; phenotype switching; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2025.04.012
  7. Nature. 2025 Jun 04.
    Loss of colonic fidelity enables multilineage plasticity and metastasis.
    Patrizia Cammareri, Michela Raponi, Yourae Hong, Caroline V Billard, Nat Peckett, Yujia Zhu, Fausto D Velez-Bravo, Nicholas T Younger, Donnchadh S Dunican, Sebastian Ö-G Pohl, Aslihan Bastem Akan, Nora J Doleschall, John Falconer, Mark White, Jean Quinn, Kathryn Pennel, Roberta Garau, Sudhir B Malla, Philip D Dunne, Richard R Meehan, Owen J Sansom, Joanne Edwards, Malcolm G Dunlop, Farhat V N Din, Sabine Tejpar, Colin W Steele, Kevin B Myant.
      Cancer cell plasticity enables the acquisition of new phenotypic features and is implicated as a major driver of metastatic progression1,2. Metastasis occurs mostly in the absence of additional genetic alterations3-5, which suggests that epigenetic mechanisms are important6. However, they remain poorly defined. Here we identify the chromatin-remodelling enzyme ATRX as a key regulator of colonic lineage fidelity and metastasis in colorectal cancer. Atrx loss promotes tumour invasion and metastasis, concomitant with a loss of colonic epithelial identity and the emergence of highly plastic mesenchymal and squamous-like cell states. Combined analysis of chromatin accessibility and enhancer mapping identified impairment of activity of the colonic lineage-specifying transcription factor HNF4A as a key mediator of these observed phenotypes. We identify squamous-like cells in human patient samples and a squamous-like expression signature that correlates with aggressive disease and poor patient prognosis. Collectively, our study defines the epigenetic maintenance of colonic epithelial identity by ATRX and HNF4A as suppressors of lineage plasticity and metastasis in colorectal cancer.
    DOI:  https://doi.org/10.1038/s41586-025-09125-5
  8. NPJ Syst Biol Appl. 2025 Jun 05. 11(1): 60
    Next generation lineage tracing and its applications to unravel development.
    Spencer Short, Rodrigo García-Tejera, Linus J Schumacher, Daniel L Coutu.
      Lineage tracing remains an essential approach towards understanding cell fate, tissue formation, and human development. Herein, we review advancements in lineage tracing techniques, the integration of sequencing and imaging technologies, and computational tools for analysis. We report on recent lineage tracing applications, including integrative techniques (MADM-CloneSeq), in situ hybridization (DART-FISH), and modern workflows (BaSISS), which hold an essential role in our aim to unravel lineage hierarchies and, ultimately, human development.
    DOI:  https://doi.org/10.1038/s41540-025-00542-w
  9. bioRxiv. 2025 May 14. pii: 2025.05.09.653038. [Epub ahead of print]
    Atlas-scale metabolic activities inferred from single-cell and spatial transcriptomics.
    Erick Armingol, James Ashcroft, Magda Mareckova, Martin Prete, Valentina Lorenzi, Cecilia Icoresi Mazzeo, Jimmy Tsz Hang Lee, Marie Moullet, Omer Ali Bayraktar, Christian Becker, Krina Zondervan, Luz Garcia-Alonso, Nathan E Lewis, Roser Vento-Tormo.
      Metabolism supplies energy, building blocks, and signaling molecules vital for cell function and communication, but methods to directly measure it at single-cell and/or spatial resolutions remain technically challenging and inaccessible for most researchers. Single-cell and spatial transcriptomics offer high-throughput data alternatives with a rich ecosystem of computational tools. Here, we present scCellFie, a computational framework to infer metabolic activities from human and mouse transcriptomic data at single-cell and spatial resolution. Applied to ~30 million cell profiles, we generated a comprehensive metabolic atlas across human organs, identifying organ- and cell-type-specific activities. In the endometrium, scCellFie reveals metabolic programs contributing to healthy tissue remodeling during the menstrual cycle, with temporal patterns replicated in data from in vitro cultures. We also uncover disease-associated metabolic alterations in endometriosis and endometrial carcinoma, linked to proinflammatory macrophages, and metabolite-mediated epithelial cell communication, respectively. Ultimately, scCellFie provides a scalable toolbox for extracting interpretable metabolic functionalities from transcriptomic data.
    DOI:  https://doi.org/10.1101/2025.05.09.653038
  10. Fam Cancer. 2025 Jun 01. 24(2): 52
    Redefining familial adenomatous polyposis: competition, cooperation, and the path to monoclonality.
    Sylvain Ferrandon, Matthew F Kalady, Sanne M van Neerven.
      Familial adenomatous polyposis (FAP) is a hereditary cancer syndrome characterized by germline mutations in the APC gene that result in the development of hundreds of premalignant adenomas throughout the colon and rectum. Prophylactic surgery remains the primary intervention strategy, as there are currently no pharmacological treatment options for FAP patients. Previous therapeutic approaches have predominantly focused on reducing polyp size rather than preventing their initiation, thereby missing a key opportunity for early intervention. Crucially, to effectively target the earliest stages of tumour development requires a deeper understanding of the molecular mechanisms underlying adenoma formation. In this review, we evaluate the latest models and methods employed to investigate the origin of FAP adenomas. We describe how mutant cells expand from their initial emergence within the intestinal epithelium and how they compete with normal cells within intestinal crypts. In addition, we discuss how multiple mutant crypts cooperate to collectively form polyclonal adenomas, and how these polyclonal lesions gradually transition towards monoclonality as adenomas progress towards colorectal cancer. Finally, we highlight how these insights inform the development of targeted cancer prevention strategies for individuals with FAP.
    Keywords:  Cancer prevention; Familial adenomatous polyposis (FAP); Intestinal adenomas; Polyclonality; Tumour initiation
    DOI:  https://doi.org/10.1007/s10689-025-00479-3
  11. bioRxiv. 2025 May 23. pii: 2025.05.23.655664. [Epub ahead of print]
    Lineage recording in monoclonal gastruloids reveals heritable modes of early development.
    Samuel G Regalado, Chengxiang Qiu, Sanjay Kottapalli, Beth K Martin, Wei Chen, Hanna Liao, Haedong Kim, Xiaoyi Li, Jean-Benoît Lalanne, Nobuhiko Hamazaki, Silvia Domcke, Junhong Choi, Jay Shendure.
      Mammalian stem cells possess a remarkable capacity for self-organization, a property that underlies increasingly sophisticated in vitro models of early development. However, even under carefully controlled conditions, stem cell-derived models exhibit substantial "inter-individual" heterogeneity. Focusing on gastruloids, a powerful model of the early posterior embryo 1 , we sought to investigate the origins of this heterogeneity. To this end, we developed a scalable protocol for generating gastruloids that are monoclonal, i.e. derived from a single mouse embryonic stem cell (mESC). Single cell transcriptional profiling of monoclonal gastruloids revealed extensive inter-individual heterogeneity, with some hardly progressing, others resembling conventional gastruloids but biased towards mesodermal or neural lineages, and yet others bearing cell types rare or absent from conventional polyclonal gastruloids. To investigate this further, we leveraged DNA Typewriter 2 to record the cell lineage relationships among the mESCs from which monoclonal gastruloids originate. Early in the expansion of "founder" mESCsーprior to induction of the resulting aggregates to form gastruloidsーwe observe clear examples of fate bias or fate restriction, i.e. sister clades that exhibit markedly different cell type compositions. In a separate experiment with DNA Typewriter, we reconstructed a monophyletic "tree of trees", composed of ∼50,000 cells derived from ∼100 gastruloids, all descended from a single "founder of founders" stem cell. From these data, we find that founder mESCs that are more closely related are more likely to give rise to monoclonal gastruloids with similar cell type compositions. Our results suggest that fluctuations in the intrinsic states of mESCs are heritable, and shape their descendants' fates across many cell divisions. Our study also showcases how DNA Typewriter can be used to reconstruct high-resolution, monophyletic cell lineage trees in stem cell models of early development.
    DOI:  https://doi.org/10.1101/2025.05.23.655664
  12. Cell Syst. 2025 Jun 02. pii: S2405-4712(25)00133-4. [Epub ahead of print] 101300
    A systems view of cellular heterogeneity: Unlocking the "wheel of fate".
    Hourieh Movasat, Enzo Giacopino, Ali Shahdoost, Yeganeh Dorri Nokoorani, Ali Houshyar Abrbekouh, Yaser Tahamtani, Nika Shakiba.
      Systems biology offers a view of the cell as an input-output device: a biochemical network (or cellular "processor") that interprets cues from the microenvironment to drive cell fate. Advancements in single-cell technologies are unlocking the cellular black box, revealing heterogeneity in seemingly homogeneous cell populations. But are these differences technical variability or biology? In this review, we explore this question through a systems biology lens, offering a framework for conceptualizing heterogeneity from the cell's perspective and summarizing systems and synthetic biology tools for capturing heterogeneity. While cellular inputs shape the probability of attaining particular fates, each cell spins a stochastic "wheel of fate." Applying this framework, we explore heterogeneity in two case studies: human pluripotent stem cell (hPSC) culture and beta cell differentiation. Looking forward, we discuss how a systems approach to heterogeneity may enable more predictable outcomes in stem cell research, with broad implications for developmental biology and regenerative medicine.
    Keywords:  cell fate; cell state; differentiation; fate bias; heterogeneity; pluripotent stem cells; single cell
    DOI:  https://doi.org/10.1016/j.cels.2025.101300
  13. bioRxiv. 2025 May 14. pii: 2025.05.09.653178. [Epub ahead of print]
    Spatial epigenomic niches underlie glioblastoma cell state plasticity.
    Sam Kint, Subhi Talal Younes, Shuozhen Bao, Gretchen Long, David Wouters, Erin Stephenson, Xing Lou, Mei Zhong, Di Zhang, Graham Su, Archibald Enninful, Mingyu Yang, Huey-Miin Chen, Katrina Ellestad, Colleen Anderson, Jennifer Moliterno, John Kelly, Jennifer A Chan, Alejandro Sifrim, Jiangbing Zhou, Ana Nikolic, Rong Fan, Marco Gallo.
      IDH -wildtype glioblastoma (GBM) is an aggressive brain tumor with poor survival and few therapeutic options. Transcriptionally-defined cell states coexist in GBM and occupy defined regions of the tumor. Evidence indicates that GBM cell states are plastic, but it remains unclear if they are determined by the underlying epigenetic state and/or by microenvironmental factors. Here, we present spatially-resolved epigenomic profiling of human GBM tissues that implicate chromatin structure as a key enabler of cell plasticity. We report two epigenetically-defined and spatially-nested tumor niches. Each niche activates short-range molecular signals to maintain its own state and, surprisingly, long-range signals to reinforce the state of the neighboring niche. The position of a cell along this gradient-like system of opposing signals determines its likelihood to be in one state or the other. Our results reveal an intrinsic system for cell plasticity that is encoded in the chromatin profiles of two adjacent niches that dot the topological architecture of GBM in cartesian space.
    DOI:  https://doi.org/10.1101/2025.05.09.653178
  14. bioRxiv. 2025 May 15. pii: 2025.05.12.653376. [Epub ahead of print]
    Organism-wide cellular dynamics and epigenomic remodeling in mammalian aging.
    Ziyu Lu, Zehao Zhang, Zihan Xu, Abdulraouf Abdulraouf, Wei Zhou, Junyue Cao.
      Aging leads to functional decline across tissues, often accompanied by profound changes in cellular composition and cell-intrinsic molecular states. However, a comprehensive catalog of how the population of individual cell types change with age and the associated epigenomic dynamics is lacking. Here, we constructed a single-cell chromatin accessibility atlas consisting of ∼7 million cells from 21 tissue types spanning three age groups in both sexes. This dataset revealed 536 main cell types and 1,828 finer-grained subtypes, defined by unique chromatin accessibility landscapes at ∼1.3 million cis-regulatory elements. We observed widespread remodeling of immune lineages, with increases in plasma cells and macrophages, and depletion of T and B cell progenitors. Additionally, non-immune cell populations, including kidney podocytes, ovary granulosa cells, muscle tenocytes and lung aerocytes, showed marked reductions with age. Meanwhile, many subtypes changed synchronously across multiple organs, underscoring the potential influence of systemic inflammatory signals or hormonal cues. At the molecular level, aging was marked by thousands of differentially accessible regions, with the most concordant changes shared across cell types linked to genes related to inflammation or development. Putative upstream factors, such as intrinsic shifts in transcription factor usages and extrinsic cytokine signatures, were identified. Notably, around 40% of aging-associated main cell types and subtypes showed sex-dependent differences, with tens of thousands of chromatin accessibility peaks altered exclusively in one sex. Together, these findings present a comprehensive framework of how aging reshapes the chromatin landscape and cellular composition across diverse tissues, offering a comprehensive resource for understanding the molecular and cellular programs underlying aging and supporting the exploration of targeted therapeutic strategies to address age-related dysfunction.
    DOI:  https://doi.org/10.1101/2025.05.12.653376
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