bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–07–27
thirteen papers selected by
Xiao Qin, University of Oxford
  1. High-resolution spatial mapping of cell state and lineage dynamics in vivo with PEtracer.
  2. From Harmony to Discord: Multicellular Coordination in Tissues and Its Rewiring in Cancer.
  3. Telocytes deliver essential Wnts directly to murine intestinal stem cells via synapse-like contacts.
  4. Modeling combinatorial regulation from single-cell multi-omics provides regulatory units underpinning cell type landscape using cRegulon.
  5. Joint representation and visualization of derailed cell states with Decipher.
  6. Intestinal tuft cell subtypes represent successive stages of maturation driven by crypt-villus signaling gradients.
  7. Experimental evolution in an era of molecular manipulation.
  8. A Meta-Review of Spatial Transcriptomics Analysis Software.
  9. The emerging role of multiomics in aging research.
  10. Challenges and opportunities for the next generation of computational tumor models.
  11. Predicting colorectal cancer risk in FAP patients using patient-specific organoids.
  12. Protocol for conducting a single-cell sequencing assay for transposase-accessible chromatin analysis.
  13. Rapamycin rescues APC-mutated colon organoid differentiation.
  1. Science. 2025 Jul 24. eadx3800
    High-resolution spatial mapping of cell state and lineage dynamics in vivo with PEtracer.
    Luke W Koblan, Kathryn E Yost, Pu Zheng, William N Colgan, Matthew G Jones, Dian Yang, Arhan Kumar, Jaspreet Sandhu, Alexandra Schnell, Dawei Sun, Can Ergen, Reuben A Saunders, Xiaowei Zhuang, William E Allen, Nir Yosef, Jonathan S Weissman.
      Charting the spatiotemporal dynamics of cell fate determination in development and disease is a long-standing objective in biology. Here we present the design, development, and extensive validation of PEtracer, a prime editing-based, evolving lineage tracing technology compatible with both single-cell sequencing and multimodal imaging methodologies to jointly profile cell state and lineage in dissociated cells or while preserving cellular context in tissues with high spatial resolution. Using PEtracer coupled with MERFISH spatial transcriptomic profiling in a syngeneic mouse model of tumor metastasis, we reconstruct the growth of individually-seeded tumors in vivo and uncover distinct modules of cell-intrinsic and cell-extrinsic factors that coordinate tumor growth. More generally, PEtracer enables systematic characterization of cell state and lineage relationships in intact tissues over biologically-relevant temporal and spatial scales.
    DOI:  https://doi.org/10.1126/science.adx3800
  2. Cancer Res. 2025 Jul 23.
    From Harmony to Discord: Multicellular Coordination in Tissues and Its Rewiring in Cancer.
    Merve Dede, Vakul Mohanty, Ken Chen.
      Tissue function emerges from coordinated interactions among diverse cell types, but how these interactions are structured and rewired in disease remains unclear. In a recent study, Shi and colleagues introduce CoVarNet, a computational framework that maps reproducible multicellular modules (CMs) across 35 human tissues using single-cell and spatial transcriptomics. These CMs, spanning immune, stromal, and endothelial cells, exhibit functional organization across tissue systems and dynamically respond to biological transitions such as aging and menopause. Importantly, cancer progression is marked by a breakdown of tissue-specific CMs and the emergence of a convergent cancer-associated ecosystem, cCM02. This rewiring reflects a fundamental reorganization of tissue architecture during malignancy and provides new opportunities for diagnostics and therapeutic targeting. The study signifies a conceptual advance from cell-centric to ecosystem-level biology and offers a generalizable framework for integrating multimodal data to dissect tissue-level coordination. Here, we discuss how CoVarNet redefines our understanding of tissue organization, its translational implications in oncology, and unresolved questions in modular tissue biology.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3155
  3. Dev Cell. 2025 Jul 19. pii: S1534-5807(25)00438-1. [Epub ahead of print]
    Telocytes deliver essential Wnts directly to murine intestinal stem cells via synapse-like contacts.
    Gediminas Greicius, Lorenz Mittermeier, Ruanyi Liang, Kristmundur Sigmundsson, Yarn Kit Chan, Pei-Ju Liao, Alexander Ludwig, David M Virshup.
      Spatial and temporal control of Wnt delivery to the intestinal stem cell niche regulates intestinal homeostasis. Telocytes, specialized stromal cells with characteristic long, thin cytoplasmic protrusions, produce essential Wnts for the development and maintenance of this niche. However, how Wnts travel from telocytes to stem cells in the gut remains unclear. Fluorescence and electron microscopy of murine telocytes co-cultured with intestinal organoids identified specialized telocyte extensions that transport and locally secrete Wnts on microvesicles and make intimate contacts with epithelial cells, reminiscent of neuronal contact-based signaling. Investigating the potential role of synapse-forming and plasma membrane-associated platform proteins, we found that depletion of either KANK1 or Liprins from telocytes markedly reduced their filopodia, compromised WNT2 presentation to epithelial cells, and impaired telocyte-dependent organoid growth. Characteristic telocyte structures facilitate Wnt delivery to the intestinal stem cell niche via synapse-like contacts.
    Keywords:  Wnt signaling; cytonemes; exovesicle; filopodia; intestinal stem cells; organoids; synapse; telocytes
    DOI:  https://doi.org/10.1016/j.devcel.2025.06.040
  4. Genome Biol. 2025 Jul 24. 26(1): 220
    Modeling combinatorial regulation from single-cell multi-omics provides regulatory units underpinning cell type landscape using cRegulon.
    Zhanying Feng, Xi Chen, Zhana Duren, Jingxue Xin, Hao Miao, Qiuyue Yuan, Yong Wang, Wing Hung Wong.
      Advances in single-cell technology enable large-scale generation of omics data, promising for clarifying gene regulatory networks governing different cell type/states. Nonetheless, prevailing methods fail to account for universal and reusable regulatory modules in GRNs, which are fundamental underpinnings of cell type landscape. We introduce cRegulon to infer regulatory modules by modeling combinatorial regulation of transcription factors based on diverse GRNs from single-cell multi-omics data. Through benchmarking and applications using simulated datasets and real datasets, cRegulon outperforms existing approaches in identifying TF combinatorial modules as regulatory units and annotating cell types. cRegulon offers new insights and methodology into combinatorial regulation.
    DOI:  https://doi.org/10.1186/s13059-025-03680-w
  5. Genome Biol. 2025 Jul 23. 26(1): 219
    Joint representation and visualization of derailed cell states with Decipher.
    Achille Nazaret, Joy Linyue Fan, Vincent-Philippe Lavallée, Cassandra Burdziak, Andrew E Cornish, Vaidotas Kiseliovas, Robert L Bowman, Ignas Masilionis, Jaeyoung Chun, Shira E Eisman, James Wang, Justin Hong, Lingting Shi, Ross L Levine, Linas Mazutis, David Blei, Dana Pe'er, Elham Azizi.
      Biological insights often depend on comparing conditions such as disease and health. Yet, we lack effective computational tools for integrating single-cell genomics data across conditions or characterizing transitions from normal to deviant cell states. Here, we present Decipher, a deep generative model that characterizes derailed cell-state trajectories. Decipher jointly models and visualizes gene expression and cell state from normal and perturbed single-cell RNA-seq data, revealing shared and disrupted dynamics. We demonstrate its superior performance across diverse contexts, including in pancreatitis with oncogene mutation, acute myeloid leukemia, and gastric cancer.
    Keywords:  Acute myeloid leukemia; Cell-state trajectories; Deep generative model; Dimensionality reduction
    DOI:  https://doi.org/10.1186/s13059-025-03682-8
  6. Nat Commun. 2025 Jul 22. 16(1): 6765
    Intestinal tuft cell subtypes represent successive stages of maturation driven by crypt-villus signaling gradients.
    Julian R Buissant des Amorie, Max A Betjes, Jochem H Bernink, Joris H Hageman, Veerle E Geurts, Harry Begthel, Dimitrios Laskaris, Maria C Heinz, Ingrid Jordens, Tiba Vinck, Ronja M Houtekamer, Ingrid Verlaan-Klink, Sascha R Brunner, Jacco van Rheenen, Martijn Gloerich, Hans Clevers, Sander J Tans, Jeroen S van Zon, Hugo J G Snippert.
      Intestinal tuft cells are epithelial sentinels that trigger host defense upon detection of parasite-derived compounds. While they represent potent targets for immunomodulatory therapies in inflammation-driven intestinal diseases, their functioning and differentiation are poorly understood. Here, we reveal common intermediary transcriptomes among the previously described tuft-1 and tuft-2 subtypes in mouse and human. Tuft cell subtype-specific reporter knock-ins in organoids show that the two subtypes reflect successive post-mitotic maturation stages within the tuft cell lineage. In vitro stimulation with interleukin-4 and 13 is sufficient to fuel the generation of new Nrep+ tuft-1 cells, arising from tuft precursors (tuft-p). Subsequently, changes in crypt-villus signaling gradients, such as BMP, and cholinergic signaling, are required to advance maturation towards Chat+ tuft-2 phenotypes. Functionally, we find chemosensory capacity to increase during maturation. Our tuft subtype-specific reporters and optimized differentiation strategy in organoids provide a platform to study immune-related tuft cell subtypes and their unique chemosensory properties.
    DOI:  https://doi.org/10.1038/s41467-025-61878-9
  7. Nat Rev Genet. 2025 Jul 21.
    Experimental evolution in an era of molecular manipulation.
    Joao A Ascensao, Michael M Desai.
      Laboratory evolution experiments in microbial and viral populations have provided great insight into the dynamics and predictability of evolution. The rise of high-throughput sequencing technologies over the past two decades has driven a massive expansion in the scale and power of these experiments. However, until recently our abilities to connect genetic with phenotypic changes and analyse the molecular basis of adaptation have remained limited. Rapid technical advances to measure and manipulate both genotypes and phenotypes are now providing opportunities to investigate the genetic basis of phenotypic evolution and the forces that drive evolutionary dynamics. Here we review how these methodological advances are being used to predict and manipulate the course of laboratory evolution, analyse eco-evolutionary interactions, and how they are beginning to bridge the gap between laboratory and natural evolution.
    DOI:  https://doi.org/10.1038/s41576-025-00867-6
  8. Cells. 2025 Jul 10. pii: 1060. [Epub ahead of print]14(14):
    A Meta-Review of Spatial Transcriptomics Analysis Software.
    Jessica Gillespie, Maciej Pietrzak, Min-Ae Song, Dongjun Chung.
      Spatial transcriptomics combines gene expression data with spatial coordinates to allow for the discovery of detailed RNA localization, study development, investigating the tumor microenvironment, and creating a tissue atlas. A large range of spatial transcriptomics software is available, with little information on which may be better suited for particular datasets or computing environments. A review was conducted to detail the useful metrics when choosing appropriate software for spatial transcriptomics analysis. Specifically, the results from benchmarking studies that compared software across four key areas of spatial transcriptomics analysis (tissue architecture identification, spatially variable gene discovery, cell-cell communication analysis, and deconvolution) were assimilated into a single review that can serve as guidance when choosing potential spatial transcriptomics analysis software.
    Keywords:  benchmarking; cell–cell communication; deconvolution; spatial transcriptomics; spatially variable gene; tissue architecture identification
    DOI:  https://doi.org/10.3390/cells14141060
  9. Epigenomics. 2025 Jul 20. 1-8
    The emerging role of multiomics in aging research.
    Douglas M Ruden.
      Aging is a complex biological process involving coordinated changes across multiple molecular systems. Traditional reductionist approaches, while valuable, are insufficient to capture the full scope of aging's systemic nature. Multiomics - integrating data from genomics, transcriptomics, epigenomics, proteomics, and metabolomics - provides a comprehensive framework to study aging as an interconnected network. In this Perspective, I explore how multiomic strategies, particularly those leveraging epigenomic and single-cell data, are reshaping our understanding of aging biology. Epigenetic alterations, including DNA methylation and histone modifications, are not only hallmarks but also powerful biomarkers of biological age. I discuss advances in multiomic aging clocks, cross-tissue atlases, and single-cell spatial technologies that decode aging at unprecedented resolution. I also build on a prior review I wrote with colleagues, Epigenomics. 2023;15(14):741-754, which introduced the concept of pathological epigenetic events that are reversible (PEERs) - epigenetic alterations linked to early-life exposures that predispose to aging and disease but may be therapeutically modifiable. This Perspective examines how PEERs and multiomics intersect to inform biomarkers, geroprotective interventions, and personalized aging medicine. Finally, I highlight integration challenges, ethical concerns, and the need for standardization to accelerate clinical translation. Together, these insights position multiomics as a central pillar in the future of aging research.
    Keywords:  DNA methylation; Multiomics; epigenomics; epitranscriptomics; hallmarks of aging and DOHaD; healthspan; histone modifications; lifespan
    DOI:  https://doi.org/10.1080/17501911.2025.2533111
  10. PLoS Biol. 2025 Jul;23(7): e3003269
    Challenges and opportunities for the next generation of computational tumor models.
    Lance L Munn, Rakesh K Jain.
      Mathematical models have become essential tools for exploring the complex interplay between cancer cells and their microenvironment, but require multidisciplinary expertise and abundant biological data to develop. AI is leading the way towards the next wave of tumor models.
    DOI:  https://doi.org/10.1371/journal.pbio.3003269
  11. Cancer Gene Ther. 2025 Jul 22.
    Predicting colorectal cancer risk in FAP patients using patient-specific organoids.
    Aline Habib, Rose Mamistvalov, Mira Malcov, Dalit Ben-Yosef.
      Colorectal cancer (CRC), a prevalent global cancer, is mostly sporadic. Familial adenomatous polyposis (FAP), arises from APC germline mutations. We established FAP-human embryonic stem cell lines (FAP1,2,3) with distinct APC mutations and differentiated them into colon organoids to study cancer development. While normal expressing APC lines and FAP3 formed complex organoids, FAP1,2 failed to differentiate. By utilizing CRISPR editing to correct APC mutations in FAP1,2, we succeeded in restoring their ability to form complex organoids expressing colon gene (CDX2). To elucidate the truncated APC proteins' mechanism of action, we used AlphaFold2 algorithm to model their secondary structures. Structural analysis of the normal phenotype organoids (normal and FAP3) revealed 5-6 salt bridges only at the N-terminal oligomerization domain. In contrast, analysis of disease organoids-phenotype (FAP1,2) revealed a production of novel salt bridges, likely act in a dominant-negative manner on full-length APC, disrupting APC function and promoting tumorigenesis. Our study underscores the critical role of germline APC mutations in colon cancer initiation, revealing how specific mutations influence disease severity. By deciphering APC structure-function relationships, we illuminate potential therapies and the molecular underpinnings of APC mutations that precede clinical presentation.
    DOI:  https://doi.org/10.1038/s41417-025-00923-7
  12. STAR Protoc. 2025 Jul 21. pii: S2666-1667(25)00366-1. [Epub ahead of print]6(3): 103960
    Protocol for conducting a single-cell sequencing assay for transposase-accessible chromatin analysis.
    Wen Ma, Peiyao Ma, Yue Yuan, Dandan Hu, Kaifeng Li, Pengfei Cai, Chuanyu Liu.
      While the single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) is a powerful single-cell resolution tool for studying chromatin accessibility, its analytical workflow presents significant challenges for researchers new to scATAC-seq. Here, we present a protocol for conducting scATAC-seq analysis using a publicly available dataset as an example. We describe steps for data pre-processing and downstream analysis. We then detail procedures for computational multi-omics integration.
    Keywords:  Bioinformatics; Sequence analysis; Single Cell
    DOI:  https://doi.org/10.1016/j.xpro.2025.103960
  13. Cancer Gene Ther. 2025 Jul 23.
    Rapamycin rescues APC-mutated colon organoid differentiation.
    Aline Habib, Rose Mamistvalov, Dalit Ben-Yosef.
      Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized by germline mutations in the adenomatous polyposis coli (APC) gene. This leads to numerous colorectal adenomas and a high risk of colorectal cancer (CRC). Our stem cell-derived colon organoid model revealed that a heterozygous APC mutation is sufficient to induce colorectal cancer formation. We found a link between APC mutation type, organoid maturation and FAP severity. Here, we show that severe germline mutations in hESCs employ diverse mechanisms of carcinogenesis. FAP1-hESCs expressing a truncated 332-amino acid protein exhibited a hyperactivated mTOR pathway, including PTEN inactivation and increased S6K1 and eIF4E activation. This affected oncogenic c-Myc expression and contributed to apoptosis resistance. Rapamycin treatment restored differentiation potential in FAP1 organoids but not FAP2 organoids, which expressed a larger truncated protein without mTOR pathway activation. Our in vitro colon organoids system findings were validated in human patients. Notably, a colon from a FAP1 patient exhibited high expression of mTOR pathway proteins. These findings highlight the potential of rapamycin for personalized therapy in FAP patients with distinct mTOR-mediated APC mutations. Our colon organoid model is valuable for studying CRC and developing new diagnostic, preventive, and therapeutic approaches to prevent or delay tumorigenesis in FAP patients.
    DOI:  https://doi.org/10.1038/s41417-025-00935-3
This page is being maintained by Thomas Krichel. It was last updated on 2025‒07‒31 at 21:55.