bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–09–28
fifteen papers selected by
Xiao Qin, University of Oxford
  1. Patient-Derived Tumor Organoids to Model Cancer Cell Plasticity and Overcome Therapeutic Resistance.
  2. Human gut evolution: insights from stem cell models and single-cell genomics.
  3. Identifying an optimal perturbation to induce a desired cell state by generative deep learning.
  4. EpiAgent: foundation model for single-cell epigenomics.
  5. Mapping transcriptional responses to cellular perturbation dictionaries with RNA fingerprinting.
  6. Identification, functional insights and therapeutic targeting of EMT tumour states.
  7. The immune microenvironment of colorectal cancer.
  8. ArchVelo: Archetypal Velocity Modeling for Single-cell Multi-omic Trajectories.
  9. Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness.
  10. SPP1 is required for maintaining mesenchymal cell fate in pancreatic cancer.
  11. The Colonic Crypt: Cellular Dynamics and Signaling Pathways in Homeostasis and Cancer.
  12. A practical guide to spatial transcriptomics: lessons from over 1000 samples.
  13. Python, the movie! The programming language's origin story comes to the silver screen.
  14. Focusing on the complex and dynamic interplay between ageing and cancer.
  15. RESTRICT-seq enables time-gated CRISPR screens and uncovers novel epigenetic dependencies of SCC resistance.
  1. Cells. 2025 Sep 18. pii: 1464. [Epub ahead of print]14(18):
    Patient-Derived Tumor Organoids to Model Cancer Cell Plasticity and Overcome Therapeutic Resistance.
    Roberto Coppo, Masahiro Inoue.
      Cancer cell plasticity, defined as the ability of tumor cells to reversibly adopt distinct functional states, plays a central role in tumor heterogeneity, therapy resistance, and disease relapse. This process enables cells to enter stem-like, dormant, or drug-tolerant persister states in response to treatment or environmental stress without undergoing genetic changes. Such reversible transitions complicate and limit current treatments. Conventional cancer models often fail to capture the complexities of these adaptive states. In contrast, patient-derived tumor organoids (PDOs), which retain the cellular diversity and structure of primary tumors, provide a unique system for investigating plasticity. This review describes how PDOs can model cellular plasticity, such as the emergence of drug-tolerant persister cells and the interconversion between cancer stem cell states across multiple tumor types. We particularly focused on colorectal cancer organoids, for which research on the mechanism of plasticity is the most advanced. Combined with single-cell analysis, lineage tracing, and functional assays, PDOs can help identify the molecular pathways that control plasticity. Understanding these mechanisms is important for developing therapies to prevent treatment failure and control disease progression.
    Keywords:  cancer stem cells; cellular plasticity; drug-tolerant persister cells; patient-derived tumor organoids; therapy resistance; tumor heterogeneity
    DOI:  https://doi.org/10.3390/cells14181464
  2. Curr Opin Genet Dev. 2025 Sep 24. pii: S0959-437X(25)00090-5. [Epub ahead of print]95 102398
    Human gut evolution: insights from stem cell models and single-cell genomics.
    Rubén López-Sandoval, Stefano Secchia, Joep Beumer, Jarrett Gray Camp.
      The gastrointestinal (GI) tract evolved in response to dietary changes and pathogen exposures that varied throughout history. As a major interface between the host and environment, the GI epithelia have evolved specialized barrier and immune functions while optimizing nutrient processing and absorption. Recent technological breakthroughs in modeling human biology in vitro and comparative single-cell genomics are providing novel insights into the genetic, cellular, and ontogenic basis of human evolution. In this review, we provide a broad overview of human-specific gut changes and how GI organoids and single-cell technologies can offer a mechanistic understanding of the specific features of human GI tract physiology.
    DOI:  https://doi.org/10.1016/j.gde.2025.102398
  3. Cell Syst. 2025 Sep 24. pii: S2405-4712(25)00238-8. [Epub ahead of print] 101405
    Identifying an optimal perturbation to induce a desired cell state by generative deep learning.
    Younghyun Han, Hyunjin Kim, Chun-Kyung Lee, Kwang-Hyun Cho.
      Controlling cell states is pivotal in biological research, yet understanding the specific perturbations that induce desired changes remains challenging. To address this, we present PAIRING (perturbation identifier to induce desired cell states using generative deep learning), which identifies cellular perturbations leading to the desired cell state. PAIRING embeds cell states in the latent space and decomposes them into basal states and perturbation effects. The identification of optimal perturbations is achieved by comparing the decomposed perturbation effects with the vector representing the transition toward the desired cell state in the latent space. We demonstrate that PAIRING can identify perturbations transforming given cell states into desired states across different types of transcriptome datasets. PAIRING is employed to identify perturbations that lead colorectal cancer cells to a normal-like state. Moreover, simulating gene expression changes using PAIRING provides mechanistic insights into the perturbation. We anticipate that it will have a broad impact on therapeutic development, potentially applicable across various biological domains.
    Keywords:  cell state control; computational biology; deep learning; perturbation identification; systems biology
    DOI:  https://doi.org/10.1016/j.cels.2025.101405
  4. Nat Methods. 2025 Sep 25.
    EpiAgent: foundation model for single-cell epigenomics.
    Xiaoyang Chen, Keyi Li, Xuejian Cui, Zian Wang, Qun Jiang, Jiacheng Lin, Zhen Li, Zijing Gao, Hairong Lv, Rui Jiang.
      Although single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) enables the exploration of the epigenomic landscape that governs transcription at the cellular level, the complicated characteristics of the sequencing data and the broad scope of downstream tasks mean that a sophisticated and versatile computational method is urgently needed. Here we introduce EpiAgent, a foundation model pretrained on our manually curated large-scale Human-scATAC-Corpus. EpiAgent encodes chromatin accessibility patterns of cells as concise 'cell sentences' and captures cellular heterogeneity behind regulatory networks via bidirectional attention. Comprehensive benchmarks show that EpiAgent excels in typical downstream tasks, including unsupervised feature extraction, supervised cell type annotation and data imputation. By incorporating external embeddings, EpiAgent enables effective cellular response prediction for both out-of-sample stimulated and unseen genetic perturbations, reference data integration and query data mapping. Through in silico knockout of cis-regulatory elements, EpiAgent demonstrates the potential to model cell state changes. EpiAgent is further extended to directly annotate cell types in a zero-shot manner.
    DOI:  https://doi.org/10.1038/s41592-025-02822-z
  5. bioRxiv. 2025 Sep 20. pii: 2025.09.19.676866. [Epub ahead of print]
    Mapping transcriptional responses to cellular perturbation dictionaries with RNA fingerprinting.
    Isabella N Grabski, Junsuk Lee, John Blair, Carol Dalgarno, Isabella Mascio, Alexandra Bradu, David A Knowles, Rahul Satija.
      Single-cell perturbation dictionaries provide systematic measurements of how cells respond to genetic and chemical perturbations, and create the opportunity to assign causal interpretations to observational data. Here, we introduce RNA fingerprinting, a statistical framework that maps transcriptional responses from new experiments onto reference perturbation dictionaries. RNA fingerprinting learns denoised perturbation "fingerprints" from single-cell data, then probabilistically assigns query cells to one or more candidate perturbations while accounting for uncertainty. We benchmark our method across ground-truth datasets, demonstrating accurate assignments at single-cell resolution, scalability to genome-wide screens, and the ability to resolve combinatorial perturbations. We demonstrate its broad utility across diverse biological settings: identifying context-specific regulators of p53 under ribosomal stress, characterizing drug mechanisms of action and dose-dependent off-target effects, and uncovering cytokine-driven B cell heterogeneity during secondary influenza infection in vivo. Together, these results establish RNA fingerprinting as a versatile framework for interpreting single-cell datasets by linking cellular states to the underlying perturbations which generated them.
    DOI:  https://doi.org/10.1101/2025.09.19.676866
  6. Nat Rev Cancer. 2025 Sep 25.
    Identification, functional insights and therapeutic targeting of EMT tumour states.
    Anqi Dong, Cédric Blanpain.
      Epithelial-to-mesenchymal transition (EMT) is a cellular process during which cells lose their epithelial characteristics and acquire mesenchymal features with enhanced migration capacities. EMT has key roles in different aspects of tumorigenesis, including tumour initiation, progression, metastasis and resistance to therapy. Here, we have reviewed the recent advances in our understanding of EMT in cancer. Instead of being a binary switch as initially proposed, EMT has been shown to be composed of multiple tumour states residing in specific niches with distinct functional properties that are controlled by different gene regulatory networks. We discuss how the types of oncogenic mutations, signalling pathways, transcription factors, epigenetic regulators and microenvironmental cues regulate the different EMT states. We also highlight the mechanisms by which EMT controls resistance to anticancer therapy and how new approaches to pharmacologically target EMT in clinical settings have recently been developed.
    DOI:  https://doi.org/10.1038/s41568-025-00873-0
  7. Nat Rev Cancer. 2025 Sep 22.
    The immune microenvironment of colorectal cancer.
    Kilian B Kennel, Florian R Greten.
      Colorectal cancer (CRC) progression depends on the close interaction of tumour cells and the tumour microenvironment (TME). Although the TME contributes to poor therapy responses and immune evasion, immune cells within the TME can be therapeutically leveraged, as exemplified by immune checkpoint blockade (ICB). Unfortunately, only a small subset of patients with CRC benefit from ICB therapy; those with immune-activated, microsatellite unstable CRC respond, whereas the predominant group of patients with CRC, those with microsatellite-stable tumours, do not. Although challenging, modulating the TME of CRC to convert these lowly immunogenic and immunosuppressed tumours into immune-activated tumours holds tremendous therapeutic potential. In this Review we provide an overview of the cellular and molecular components of immunity in the TME of CRCs at various stages of disease as well as the mechanisms of immunosuppression and immune evasion. We further describe how systemic and local therapies for CRC impact the tumour and systemic immune microenvironments, and how immunity could serve as a therapeutic and prognostic biomarker. Lastly, we highlight novel immunotherapeutic strategies and approaches that modulate the TME of CRCs to make them amenable to immunotherapy.
    DOI:  https://doi.org/10.1038/s41568-025-00872-1
  8. bioRxiv. 2025 Sep 17. pii: 2025.09.14.676182. [Epub ahead of print]
    ArchVelo: Archetypal Velocity Modeling for Single-cell Multi-omic Trajectories.
    Maria Avdeeva, Sarah Walker, Joris van der Veeken, Alexander Rudensky, Yuri Pritykin.
      Inferring dynamic cellular processes from static single-cell measurements remains a central challenge in genomics. Here we introduce ArchVelo, a new method for modeling gene regulation and inferring cell trajectories using single-cell simultaneous chromatin accessibility (scATAC-seq) and transcriptomic (scRNA-seq) profiling. ArchVelo represents chromatin accessibility as a set of archetypes-shared regulatory programs-and models their dynamic influence on transcription. Compared to previous methods, ArchVelo improves inference accuracy and gene-level latent time alignment, and enables identification of the underlying transcription factor activity. We benchmark ArchVelo on developing mouse brain and human hematopoiesis datasets and apply it to CD8 T cells responding to viral infection, revealing distinct trajectories of differentiation and proliferation. Focusing on the progenitor CD8 T cell population with key roles in sustaining immune responses and translationally linked to immunotherapy outcomes, we identify a previously uncharacterized differentiation trajectory from Ccr6 - to Ccr6 + progenitors, shared between acute and chronic infection. In sum, ArchVelo provides a principled framework for modeling dynamic gene regulation in multi-omic single-cell data across biological systems.
    DOI:  https://doi.org/10.1101/2025.09.14.676182
  9. Science. 2025 Sep 25. eadl1988
    Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness.
    Brian D Cosgrove, Lexi R Bounds, Carson Key Taylor, Alan L Su, Anthony J Rizzo, Alejandro Barrera, Tongyu Sun, Alexias Safi, Lingyun Song, Thomas Whitlow, Aleksandra Tata, Nahid Iglesias, Yarui Diao, Purushothama Rao Tata, Brenton D Hoffman, Gregory E Crawford, Charles A Gersbach.
      Epigenetic control of gene expression and cellular phenotype is influenced by changes in the local microenvironment, yet how mechanical cues precisely influence epigenetic state to regulate transcription remains largely unmapped. Here, we combine genome-wide epigenome profiling, epigenome editing, and phenotypic and single-cell RNA-seq CRISPR screening to identify a class of genomic enhancers that responds to the mechanical microenvironment. These "mechanoenhancers" can be preferentially activated on either soft or stiff extracellular matrix contexts and regulate transcription to influence critical cell functions including apoptosis, adhesion, proliferation, and migration. Epigenetic editing of mechanoenhancers reprograms the cellular response to the mechanical microenvironment and modulates the activation of disease-related genes in lung fibroblasts from healthy and fibrotic donors. Epigenetic editing of mechanoenhancers holds potential for precise targeting of mechanically-driven diseases.
    DOI:  https://doi.org/10.1126/science.adl1988
  10. Nature. 2025 Sep 24.
    SPP1 is required for maintaining mesenchymal cell fate in pancreatic cancer.
    Huafu Li, Linxiang Lan, Hengxing Chen, May Zaw Thin, Hari Ps, Jessica K Nelson, Ian M Evans, E Josue Ruiz, Rongjie Cheng, Li Tran, Mark Allen, Jian Ma, Tingzhuang Yi, Chunming Wang, Yulong He, Naomi Guppy, Anguraj Sadanandam, Shao-Zhen Lin, Changhua Zhang, Axel Behrens.
      Elucidating the complex network of communication between tumour cells is central to understanding cell fate decisions and progression of pancreatic ductal adenocarcinoma (PDAC)1,2. We previously showed that constant suppression of BMP activity by the BMP antagonist GREM1 secreted by mesenchymal PDAC cells is essential for maintaining the fate of epithelial PDAC cells3. Here we identify SPP1 (also known as osteopontin)4 as a key regulator of mesenchymal cell fate in pancreatic cancer. Proteomic analysis of plasma from patients with PDAC showed that SPP1 is substantially upregulated in late-stage disease. Inactivation of Spp1 led to a delay in tumorigenesis in mouse PDAC models and abolished metastasis formation. Spp1 was expressed in epithelial PDAC cells, and Spp1 inactivation resulted in a conversion of mesenchymal to epithelial PDAC cells. Mechanistically, SPP1 bound the CD61 receptor on mesenchymal PDAC cells to induce Bmp2 and Grem1 expression, and GREM1 inhibition of BMP signalling was required for Spp1 expression in epithelial cells, thereby forming an intercellular regulatory loop. Concomitant inactivation of Grem1 reverted the epithelial phenotype of Spp1 knockout to fully mesenchymal PDAC. Conversely, Grem1 heterozygosity combined with Spp1 knockout resulted in wild-type PDAC histology, a result that confirmed the direct antagonistic functions of these factors. Hence, mesenchymal and epithelial PDAC cell fates are determined by the reciprocal paracrine regulation of the soluble factors GREM1 and SPP1.
    DOI:  https://doi.org/10.1038/s41586-025-09574-y
  11. Cells. 2025 Sep 11. pii: 1428. [Epub ahead of print]14(18):
    The Colonic Crypt: Cellular Dynamics and Signaling Pathways in Homeostasis and Cancer.
    Anh L Nguyen, Molly A Lausten, Bruce M Boman.
      The goal of this review is to expand our understanding of how the cellular organization of the normal colonic crypt is maintained and elucidate how this intricate architecture is disrupted during tumorigenesis. Additionally, it will focus on implications for new therapeutic strategies targeting Epithelial-Mesenchymal Transition (EMT). The colonic crypt is a highly structured epithelial unit that functions in maintaining homeostasis through a complex physiological function of diverse cell types: SCs, transit-amplifying (TA) progenitors, goblet cells, absorptive colonocytes, Paneth-like cells, M cells, tuft cells, and enteroendocrine cells. These cellular subpopulations are spatially organized and regulated by multiple crucial signaling pathways, including WNT, Notch, Bone Morphogenetic Protein (BMP), and Fibroblast Growth Factor (FGF). Specifically, we discuss how these regulatory networks control the precise locations and functions of crypt cell types that are necessary to achieve cellular organization and homeostasis in the normal colon crypt. In addition, we detail how the crypt's hierarchical structure is profoundly perturbed in colorectal cancer (CRC) development. Tumorigenesis appears to be driven by LGR5+ cancer stem cells (CSCs) and the hyperproliferation of TA cells as colonocytes undergo metabolic reprogramming. Goblet cells lose their secretory phenotype, while REG4+ Paneth-like cells foster SC niches. Tumor microenvironment is also disrupted by upregulation of M cells and by tumor-immune crosstalk that is promoted by tuft cell expansion. Moreover, the presence of enteroendocrine cells in CRC has been implicated in treatment resistance due to its contribution to tumor heterogeneity. These cellular changes are caused by the disruption of homeostasis signaling whereby: overactivation of WNT/β-catenin promotes stemness, dysregulation of Notch inhibits differentiation, suppression of BMP promotes hyperproliferation, and imbalance of FGF/WNT/BMP/NOTCH enhances cellular plasticity and invasion. Further discussion of emerging therapies targeting epithelial markers and regulatory factors, emphasizing current development in novel, precision-based approaches in CRC treatment is also included.
    Keywords:  M cells; Paneth-like cells; colonic crypt; colorectal cancer; enteroendocrine cells; epithelial–mesenchymal transition; goblet cells; signaling pathways; stem cells; tuft cells
    DOI:  https://doi.org/10.3390/cells14181428
  12. Trends Biotechnol. 2025 Sep 19. pii: S0167-7799(25)00357-9. [Epub ahead of print]
    A practical guide to spatial transcriptomics: lessons from over 1000 samples.
    Daniela Grases, Eduard Porta-Pardo.
      Spatial transcriptomics (ST) enables the  in situ mapping of gene expression, revolutionizing our ability to study tissue organization and cellular interactions. However, many groups struggle with practical barriers to implementation, including platform selection, sample quality, and experimental scalability. We provide a practical guide to ST, informed by the processing and analysis of over 1000 spatial samples across multiple ST platforms. We outline best practices for experimental design, tissue handling, sequencing, and computational analysis, with special attention to clinical samples. Our goal is to translate hands-on experience into recommendations that support robust, reproducible spatial workflows. This guide is designed to assist researchers at all levels: from those designing their first spatial experiment to groups aiming to integrate ST into large-scale studies.
    Keywords:  Visium; Xenium; best practices; experimental design; spatial omics; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.tibtech.2025.08.020
  13. Nature. 2025 Sep 25.
    Python, the movie! The programming language's origin story comes to the silver screen.
    Jeffrey M Perkel.
      
    Keywords:  Arts; Computational biology and bioinformatics; Computer science; Technology
    DOI:  https://doi.org/10.1038/d41586-025-02903-1
  14. Nat Rev Cancer. 2025 Oct;25(10): 749-750
    Focusing on the complex and dynamic interplay between ageing and cancer.
      
    DOI:  https://doi.org/10.1038/s41568-025-00870-3
  15. bioRxiv. 2025 Sep 20. pii: 2025.09.17.676440. [Epub ahead of print]
    RESTRICT-seq enables time-gated CRISPR screens and uncovers novel epigenetic dependencies of SCC resistance.
    Selahattin Can Ozcan, Dreyton G Amador, Justin Anthony Powers, Ashley G Njiru, Zahra Ansari, Yvon Woappi.
      Cancer cell evasion of therapy is a highly adaptive process that undermines the efficacy of many treatment strategies. A significant milestone in the study of these mechanisms has been the advent of pooled CRISPR knockout screens, which enable high-throughput, genome-wide interrogations of tumor dependencies and synthetic lethal interactions, advancing our understanding of how cancer cells adapt to and evade therapies. However, the utility of this approach diminishes when applied to dynamic biological contexts, where processes are transient and sensitivity to routine cell culture manipulations that introduce noise and limit meaningful discoveries. To overcome these limitations, we present RESTRICT-seq, a next-generation pooled screening methodology that restricts Cas9 nuclear activation in controlled, repeated cycles. By confining Cas9 catalytic activity to strict temporal windows, RESTRICT-seq mitigates undesired fitness penalties that routinely accumulate throughout pooled screens. When benchmarked against conventional pooled screens and standard inducible protocols, RESTRICT-seq revealed significantly fewer divergent cell clones and increased signal-to-noise ratio, overcoming a key limitation of traditional methods. Leveraging RESTRICT-seq, we conducted a comprehensive functional survey of the druggable mammalian epigenome, uncovering several elusive epigenetic drivers of treatment resistance in cutaneous squamous cell carcinoma (cSCC). This revealed PAK1 as a previously unrecognized mediator of cSCC resistance in human and mouse SCC, offering new insights into a prognostic marker and therapeutic target of high clinical significance. Our findings establish RESTRICT-seq as a powerful tool for extending the applicability of pooled CRISPR screens to dynamic and previously intractable biological contexts.
    DOI:  https://doi.org/10.1101/2025.09.17.676440
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