bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–03–22
twelve papers selected by
Xiao Qin, University of Oxford
  1. Generalist biological artificial intelligence in modeling the language of life.
  2. CellVoyager: AI CompBio agent generates new insights by autonomously analyzing biological data.
  3. Cancer in 4D: toward Spatiotemporal Hallmark Ecosystems.
  4. Paired patient-derived organoids reveal transcription factor-driven epigenetic remodeling in breast cancer metastasis.
  5. Colorectal Cancer Is Increasing in Younger Adults.
  6. Functional chromatin signatures premark future lineage-specific enhancers.
  7. Not Just Soft: Cell Viscosity Emerges as a Driver of Tumor Cell Dissemination.
  8. LazySlide: accessible and interoperable whole-slide image analysis.
  9. Optimizing colorectal cancer screening through polygenic risk score-based risk stratification: evidence from a population-based cohort and screening trial.
  10. Ageing influences tumour-niche interactions: Implications for metastatic dormancy, reawakening and recurrence.
  11. Organoid Perturbations as Tools to Explore Cellular Function and Plasticity.
  12. The pre-metastatic niche: mechanisms, heterogeneity, and therapeutic opportunities.
  1. Nat Biotechnol. 2026 Mar 20.
    Generalist biological artificial intelligence in modeling the language of life.
    Vishwanatha M Rao, Serena Zhang, Brian S Plosky, Patrick D Hsu, Bo Wang, James Zou, Marinka Zitnik, Eric J Topol, Pranav Rajpurkar.
      Generalist biological artificial intelligence (GBAI) represents a transformative approach to modeling the 'language of life'-the flow of information from DNA to cellular function. This Review synthesizes rapid advances in biological AI to interpret and generate DNA, RNA, proteins and cellular systems. We chart a course toward comprehensive systems that can concurrently process and predict across these domains, performing several critical biological tasks simultaneously. Substantial opportunities lie in synergizing language and structural AI, leveraging specialized models and improving AI agents for autonomous discovery. After addressing challenges in data, biological complexity, scalability and experimental validation, GBAI has the potential to deepen our understanding of disease pathways and biomarkers, advance automated therapeutic design and evaluation, and integrate within virtual cells to meaningfully simulate biological activity.
    DOI:  https://doi.org/10.1038/s41587-026-03064-w
  2. Nat Methods. 2026 Mar 17.
    CellVoyager: AI CompBio agent generates new insights by autonomously analyzing biological data.
    Samuel Alber, Bowen Chen, Eric Sun, Alina Isakova, Aaron J Wilk, James Zou.
      Modern biology increasingly relies on complex, high-dimensional datasets such as single-cell RNA sequencing (scRNA-seq), which present a vast space of potential hypotheses. Systematically exploring this space is often impractical, as scRNA-seq analyses are time-consuming and require substantial computational and domain expertise. To address this challenge, we introduce CellVoyager, an AI agent built on large language models that autonomously generates and implements scRNA-seq analyses within a Jupyter notebook environment. We evaluate CellVoyager on CellBench, a benchmark of 76 published scRNA-seq studies, where it outperforms GPT-4o and o3-mini by up to 23% in predicting which analyses authors ultimately conducted, given only the papers' background sections. Across three in-depth case studies, CellVoyager generated novel findings in COVID-19, cell-cell communication and aging that experts consistently rated as creative and scientifically sound. These results demonstrate CellVoyager's potential to accelerate computational biology and uncover missing insights by autonomously analyzing biological data at scale.
    DOI:  https://doi.org/10.1038/s41592-026-03029-6
  3. Trends Cancer. 2026 Mar 16. pii: S2405-8033(26)00004-X. [Epub ahead of print]
    Cancer in 4D: toward Spatiotemporal Hallmark Ecosystems.
    Mustafa Sibai, Martin Zacharias, Nicholas McGranahan, Mariam Jamal-Hanjani, Eduard Porta-Pardo.
      The Hallmarks of Cancer framework provided a unifying description of tumor capabilities, but in its static form, it cannot capture where in a tumor these traits occur, when they arise, or how they reorganize under selection pressure. Here, we propose Spatiotemporal Hallmark Ecosystems as a new lens that redefines the functional unit of selection in cancer evolution. In this view, hallmarks are not fixed consequences of mutations but context-dependent phenotypes that are enabled or constrained by local tissue and microenvironmental conditions. This perspective resolves critical paradoxes, explaining why identical mutations yield divergent outcomes, why premalignant states persist without transformation, and how therapeutic resistance emerges not just from clonal selection but also from 'ecological buffering' by the tumor architecture. By shifting the analysis from the individual cell to the ecosystem, we outline a path toward predictive biomarkers and spatially aware strategies that target the structural stability of the tumor.
    DOI:  https://doi.org/10.1016/j.trecan.2026.01.004
  4. Cell Stem Cell. 2026 Mar 16. pii: S1934-5909(26)00077-9. [Epub ahead of print]
    Paired patient-derived organoids reveal transcription factor-driven epigenetic remodeling in breast cancer metastasis.
    Xinxin Rao, Jingwen Wang, Zhibin Qiao, Lei Hong, Mengxue Qiao, Liangwei Ni, Aixia Song, Yun Deng, Xu Zhao, Jin Meng, Xingxing Chen, Yifan Zhou, Jingyan Xue, Yayun Chi, Xinrui Wang, Zhaowei Yu, Qianqian Chen, Congling Xu, Shuang Tang, Jing Hu, Midie Xu, Wei Xu, Zhen Zhang, Yong Zhang, Yanhui Xu, Yi-Zhou Jiang, Jiong Wu, Minhong Shen, Xiaomao Guo, Xiaoli Yu, Fei Xavier Chen.
      Breast cancer exhibits marked clinical heterogeneity and dynamic epigenetic reprogramming during tumor progression, yet current subtyping approaches fail to capture molecular changes associated with metastasis. Here, we establish a comprehensive biobank of patient-derived organoids (PDOs) from matched primary tumors, adjacent normal tissues, and lymph node metastases. Integrated genomic, transcriptomic, and epigenetic analyses demonstrate that these PDOs preserve tumor-specific molecular signatures and recapitulate epigenetic remodeling during disease evolution. Epigenetic profiling defines four distinct clusters, characterized by unique transcription factor (TF) networks, pathway activities, and therapeutic vulnerabilities not fully represented by conventional classifications. The lymph node metastasis cluster, predominantly comprising metastatic PDOs, displays extensive chromatin remodeling driven by metastasis-enriched TFs, whose depletion markedly impairs spontaneous metastasis in vivo. Together, these findings establish PDO-based epigenetic characterization as a platform for elucidating regulatory mechanisms underlying breast cancer progression and for advancing precision therapeutic strategies.
    Keywords:  BHLHA15; TFAP4; breast cancer; epigenetic remodeling; epigenetics; metastasis; patient-derived organoids; transcription factors
    DOI:  https://doi.org/10.1016/j.stem.2026.02.007
  5. JAMA. 2026 Mar 20.
    Colorectal Cancer Is Increasing in Younger Adults.
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2026.1017
  6. Cell Genom. 2026 Mar 18. pii: S2666-979X(26)00051-0. [Epub ahead of print] 101189
    Functional chromatin signatures premark future lineage-specific enhancers.
    Julian Pulecio, Zakieh Tayyebi, Dingyu Liu, Wilfred Wong, Renhe Luo, Jeyaram R Damodaran, Samuel J Kaplan, Nan Hu, Hyein S Cho, Jielin Yan, Dylan Murphy, Robert W Rickert, Abhijit Shukla, Aaron Zhong, Denis Torre, Qianzi Li, Federico González, Dexin Yang, Wenbo Li, Ting Zhou, Effie Apostolou, Christina S Leslie, Danwei Huangfu.
      It remains unknown whether early embryonic cells harbor a blueprint for future enhancers that regulate the expression of lineage-specific genes in adult tissues. Here, we demonstrate that embryonic stem cells (ESCs) have transcriptionally competent chromatin regions (CCRs) prepared to induce the expression of lineage genes prior to differentiation. CCRs represent activatable pre-enhancers within the topological chromatin domains of lineage genes, marked by chromatin signatures distinguishable from primed/poised enhancers, enabling their genome-wide identification. The pioneer transcription factor (TF) FOXA2 preferentially binds CCRs during early lineage specification, promoting their conversion into active enhancers. CCRs can be harnessed to boost the expression of master TFs and promote the direct reprogramming of ESCs into differentiated cells, showcasing their potential for practical applications. Our findings identify a mechanism by which ESCs rapidly establish enhancer activity during early lineage differentiation and expand our understanding of the epigenetic features supporting transcriptional regulation and cellular plasticity.
    Keywords:  CRISPR; chromatin; developmental competence; embryonic stem cells; epigenetics; gene regulation; lineage specification; pluripotency
    DOI:  https://doi.org/10.1016/j.xgen.2026.101189
  7. Cancer Res. 2026 Mar 16.
    Not Just Soft: Cell Viscosity Emerges as a Driver of Tumor Cell Dissemination.
    Sanjiban Nath, Debanik Choudhury, Alice Amitrano, Konstantinos Konstantopoulos.
      The mechanical properties of cells and tissues have emerged as important biophysical markers for distinguishing between healthy and diseased states. In cancer, mechanical heterogeneity spans multiple scales, from tissue-level variations to substantial differences between individual tumor cells. The prevailing notion is that metastatic cancer cells are typically elastically softer than their non-malignant counterparts, a feature attributed to their ability to deform, remodel their shape, and navigate dense extracellular matrices and constricting blood vessels. However, cells are not purely elastic materials, but instead they exhibit viscoelastic behavior, in which deformation depends not only on instantaneous stiffness but also on time-dependent internal flow. In this context, Gensbittel and colleagues find that cellular viscosity, rather than elasticity, is a key determinant of cancer cell dissemination and extravasation, providing new insights into the mechanical underpinnings of cancer metastasis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-1081
  8. Nat Methods. 2026 Mar 20.
    LazySlide: accessible and interoperable whole-slide image analysis.
    Yimin Zheng, Ernesto Abila, Eva Chrenková, Iva Buljan, Juliane Winkler, André F Rendeiro.
      Histopathological data are foundational in both biological research and clinical diagnostics but remain siloed from modern multimodal and single-cell frameworks. Here we introduce LazySlide, an open-source Python package built on the scverse ecosystem for efficient whole-slide image analysis and multimodal integration. By leveraging vision-language foundation models and adhering to scverse data standards, LazySlide bridges histopathology with omics workflows. It supports tissue and cell segmentation, feature extraction, cross-modal querying and zero-shot classification, with minimal setup.
    DOI:  https://doi.org/10.1038/s41592-026-03044-7
  9. Genome Med. 2026 Mar 19.
    Optimizing colorectal cancer screening through polygenic risk score-based risk stratification: evidence from a population-based cohort and screening trial.
    Hongda Chen, Jiahui Si, Chenyu Luo, Jianbo Tian, Junyi Xin, Canqing Yu, Dianjianyi Sun, Pei Pei, Ling Yang, Iona Y Millwood, Robin G Walters, Yiping Chen, Huaidong Du, Zhengming Chen, Liming Li, Masaru Koido, Yoichiro Kamatani, Meilin Wang, Xiaoping Miao, Jun Lv, Min Dai.
      
    Keywords:  Colorectal cancer; Polygenic risk score; Precise screening; Risk prediction
    DOI:  https://doi.org/10.1186/s13073-026-01623-z
  10. Curr Opin Cell Biol. 2026 Mar 18. pii: S0955-0674(26)00018-9. [Epub ahead of print]100 102630
    Ageing influences tumour-niche interactions: Implications for metastatic dormancy, reawakening and recurrence.
    Gillian M Mackie, Frances K Turrell.
      Many cancer patients remain at risk of metastatic relapse for the remainder of their lives, despite initial disease remission, due to disseminated tumour cells (DTCs) persisting at secondary sites in a dormant, therapy-resistant state. Dormant DTCs can reawaken and develop into clinical metastasis after a prolonged latency period. Interactions between DTCs and their niche are key to metastatic dormancy and subsequent reawakening and outgrowth. Ageing has profound effects on tissues and the immune system and, as such, the field is evolving to delineate the impact of an aged microenvironment on metastatic dormancy. We summarise the latest insights in this review, focussing on recent advances in immune- and stroma-mediated regulation of dormancy and reawakening in the context of age-related microenvironmental perturbations.
    DOI:  https://doi.org/10.1016/j.ceb.2026.102630
  11. Annu Rev Genomics Hum Genet. 2026 Mar 20.
    Organoid Perturbations as Tools to Explore Cellular Function and Plasticity.
    Katharina E Kohl, Georg A Busslinger.
      Organoids have reshaped biomedical research by providing stem cell-derived model systems that capture key aspects of tissue organization, homeostasis, and disease. Their physiological relevance and adaptability have made them indispensable tools for studying development, regeneration, and tumor biology under controlled experimental conditions. This is particularly powerful in the human setting, where organoids offer an experimentally accessible alternative to in vivo studies that are ethically and practically unfeasible. Central to their success is the ability to apply diverse perturbation strategies, ranging from targeted genetic edits and pharmacological interventions to microenvironmental and biomechanical manipulations, that reveal the molecular logic of cellular and tissue function. In this review, we discuss the current landscape of organoid perturbation studies, highlighting methodological advances, representative applications, and what these efforts have taught us about cellular behavior in complex systems. By outlining methodological innovations and conceptual insights, we aim to establish a framework for using organoids not only as descriptive models but as predictive systems for probing and engineering human tissue behavior.
    DOI:  https://doi.org/10.1146/annurev-genom-120324-024252
  12. Mol Cancer. 2026 Mar 17.
    The pre-metastatic niche: mechanisms, heterogeneity, and therapeutic opportunities.
    Xu-Ran Zhang, Bing Wei, Bing-Hua Jiang, Wei-Hong Ren.
      Metastasis remains the leading cause of cancer-related mortality. The concept of the pre-metastatic niche (PMN) has provided a new framework for understanding how tumors establish favorable conditions in distant organs before metastatic colonization. This review delineates the cellular and molecular hallmarks of PMN, including immune suppression, vascular/lymphatic remodeling, metabolic reprogramming, and stromal reorganization, and traces their spatiotemporal evolution from initiation to colonization. It further examines the origins of metastatic lesions, with a focus on circulating tumor cells (CTCs) and stromal stem-like cells, highlights the pivotal role of extracellular vesicles (EVs) in mediating intercellular communication, metabolic reprogramming, and therapeutic applications. Deciphering the immune and stromal determinants of PMN formation offers key mechanistic insight into organ-specific metastasis. Consequently, this review explores translational strategies targeting the PMN, such as biomarker development, spatiotemporal profiling aided by artificial intelligence (AI), and immune, metabolic, or EV-based interventions. Deciphering PMN biology is therefore poised to open new avenues for the early interception and treatment of metastasis.
    Keywords:  Extracellular vesicles; Immune remodeling; Metabolic reprogramming; Pre-metastatic niche; Spatiotemporal evolution
    DOI:  https://doi.org/10.1186/s12943-026-02645-2
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