bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–03–23
twelve papers selected by
Xiao Qin, University of Oxford
  1. Quantitative characterization of cell niches in spatially resolved omics data.
  2. Self-organization of mouse embryonic stem cells into reproducible pre-gastrulation embryo models via CRISPRa programming.
  3. Exploring Screening for Colorectal Cancer.
  4. Identifying cross-lineage dependencies of cell-type-specific regulators in mouse gastruloids.
  5. Optimal Approach to Colorectal Cancer Screening.
  6. Signaling and transcriptional dynamics underlying early adaptation to oncogenic BRAF inhibition.
  7. Toward single-molecule protein sequencing using nanopores.
  8. SPARROW reveals microenvironment-zone-specific cell states in healthy and diseased tissues.
  9. Epigenetic regulation of reprogramming and pluripotency: insights from histone modifications and their implications for cancer stem cell therapies.
  10. The end of the genetic paradigm of cancer.
  11. Unraveling the hidden complexity of cancer through long-read sequencing.
  12. Mutations that accrue through life set the stage for stomach cancer.
  1. Nat Genet. 2025 Mar 18.
    Quantitative characterization of cell niches in spatially resolved omics data.
    Sebastian Birk, Irene Bonafonte-Pardàs, Adib Miraki Feriz, Adam Boxall, Eneritz Agirre, Fani Memi, Anna Maguza, Anamika Yadav, Erick Armingol, Rong Fan, Gonçalo Castelo-Branco, Fabian J Theis, Omer Ali Bayraktar, Carlos Talavera-López, Mohammad Lotfollahi.
      Spatial omics enable the characterization of colocalized cell communities that coordinate specific functions within tissues. These communities, or niches, are shaped by interactions between neighboring cells, yet existing computational methods rarely leverage such interactions for their identification and characterization. To address this gap, here we introduce NicheCompass, a graph deep-learning method that models cellular communication to learn interpretable cell embeddings that encode signaling events, enabling the identification of niches and their underlying processes. Unlike existing methods, NicheCompass quantitatively characterizes niches based on communication pathways and consistently outperforms alternatives. We show its versatility by mapping tissue architecture during mouse embryonic development and delineating tumor niches in human cancers, including a spatial reference mapping application. Finally, we extend its capabilities to spatial multi-omics, demonstrate cross-technology integration with datasets from different sequencing platforms and construct a whole mouse brain spatial atlas comprising 8.4 million cells, highlighting NicheCompass' scalability. Overall, NicheCompass provides a scalable framework for identifying and analyzing niches through signaling events.
    DOI:  https://doi.org/10.1038/s41588-025-02120-6
  2. Cell Stem Cell. 2025 Mar 19. pii: S1934-5909(25)00083-9. [Epub ahead of print]
    Self-organization of mouse embryonic stem cells into reproducible pre-gastrulation embryo models via CRISPRa programming.
    Gerrald A Lodewijk, Sayaka Kozuki, Clara J Han, Benjamin R Topacio, Seungho Lee, Lily Nixon, Abolfazl Zargari, Gavin Knight, Randolph Ashton, Lei S Qi, S Ali Shariati.
      Embryonic stem cells (ESCs) can self-organize into structures with spatial and molecular similarities to natural embryos. During development, embryonic and extraembryonic cells differentiate through activation of endogenous regulatory elements while co-developing via cell-cell interactions. However, engineering regulatory elements to self-organize ESCs into embryo models remains underexplored. Here, we demonstrate that CRISPR activation (CRISPRa) of two regulatory elements near Gata6 and Cdx2 generates embryonic patterns resembling pre-gastrulation mouse embryos. Live single-cell imaging revealed that self-patterning occurs through orchestrated collective movement driven by cell-intrinsic fate induction. In 3D, CRISPRa-programmed embryo models (CPEMs) exhibit morphological and transcriptomic similarity to pre-gastrulation mouse embryos. CPEMs allow versatile perturbations, including dual Cdx2-Elf5 activation to enhance trophoblast differentiation and lineage-specific activation of laminin and matrix metalloproteinases, uncovering their roles in basement membrane remodeling and embryo model morphology. Our findings demonstrate that minimal intrinsic epigenome editing can self-organize ESCs into programmable pre-gastrulation embryo models with robust lineage-specific perturbation capabilities.
    Keywords:  CRISPRa; Collective Motion; embryo models; embryonic patterning; epigenome editing; synthetic biology
    DOI:  https://doi.org/10.1016/j.stem.2025.02.015
  3. Gastroenterol Hepatol (N Y). 2025 Mar;21(3): 142
    Exploring Screening for Colorectal Cancer.
    Gary R Lichtenstein.
      
  4. Dev Cell. 2025 Mar 11. pii: S1534-5807(25)00118-2. [Epub ahead of print]
    Identifying cross-lineage dependencies of cell-type-specific regulators in mouse gastruloids.
    Luca Braccioli, Teun van den Brand, Noemi Alonso Saiz, Charis Fountas, Patrick H N Celie, Justina Kazokaitė-Adomaitienė, Elzo de Wit.
      Correct gene expression levels are crucial for normal development. Advances in genomics enable the inference of gene regulatory programs active during development but cannot capture the complex multicellular interactions occurring during mammalian embryogenesis in utero. In vitro models of mammalian development, like gastruloids, can overcome this limitation. Using time-resolved single-cell chromatin accessibility analysis, we delineated the regulatory profile during mouse gastruloid development, identifying critical drivers of developmental transitions. Gastruloids develop from bipotent progenitor cells driven by the transcription factors (TFs) OCT4, SOX2, and TBXT, differentiating into the mesoderm (characterized by the mesogenin 1 [MSGN1]) and spinal cord (characterized by CDX2). ΔCDX gastruloids fail to form spinal cord, while Msgn1 ablation inhibits paraxial mesoderm and spinal cord development. Chimeric gastruloids with ΔMSGN1 and wild-type cells formed both tissues, indicating that inter-tissue communication is necessary for spinal cord formation. Our work has important implications for studying inter-tissue communication and gene regulatory programs in development.
    Keywords:  chromatin accessibility; gastruloid; inter-tissue communication; mesoderm; single-cell ATAC-seq; spinal cord; transcription factor
    DOI:  https://doi.org/10.1016/j.devcel.2025.02.013
  5. Gastroenterol Hepatol (N Y). 2025 Mar;21(3): 163-171
    Optimal Approach to Colorectal Cancer Screening.
    Christina Wang, Aasma Shaukat.
      Rates of colorectal cancer (CRC) screening in the United States continue to fall short of guideline-recommended benchmarks. Challenges to increasing CRC screening include racial disparities, barriers at multiple levels of the health care system, and inadequate completion of 2-step screening. With new options for CRC screening and employment of programmatic strategies for screening by physicians, patients will have more opportunities to initiate and complete testing, which can ultimately improve CRC detection and prevention. This article highlights the current state of and optimal approach to CRC screening.
    Keywords:  Colorectal cancer; colonoscopy; screening modalities; stool-based tests
  6. Cell Syst. 2025 Mar 17. pii: S2405-4712(25)00072-9. [Epub ahead of print] 101239
    Signaling and transcriptional dynamics underlying early adaptation to oncogenic BRAF inhibition.
    Cameron T Flower, Chunmei Liu, Hui-Yu Chuang, Xiaoyang Ye, Hanjun Cheng, James R Heath, Wei Wei, Forest M White.
      A major contributor to poor sensitivity to anti-cancer kinase inhibitor therapy is drug-induced cellular adaptation, whereby remodeling of signaling and gene regulatory networks permits a drug-tolerant phenotype. Here, we resolve the scale and kinetics of critical subcellular events following oncogenic kinase inhibition and preceding cell cycle re-entry, using mass spectrometry-based phosphoproteomics and RNA sequencing (RNA-seq) to monitor the dynamics of thousands of growth- and survival-related signals over the first minutes, hours, and days of oncogenic BRAF inhibition in human melanoma cells. We observed sustained inhibition of the BRAF-ERK axis, gradual downregulation of cell cycle signaling, and three distinct, reversible phase transitions toward quiescence. Statistical inference of kinetically defined regulatory modules revealed a dominant compensatory induction of SRC family kinase (SFK) signaling, promoted in part by excess reactive oxygen species, rendering cells sensitive to co-treatment with an SFK inhibitor in vitro and in vivo, underscoring the translational potential for assessing early drug-induced adaptive signaling. A record of this paper's transparent peer review process is included in the supplemental information.
    Keywords:  BRAF; SRC family kinase signaling; cancer systems biology; drug adaptation; gene regulatory network; kinase inhibition; melanoma; multi-omics integration; oncogenic signaling; phosphoproteomics
    DOI:  https://doi.org/10.1016/j.cels.2025.101239
  7. Nat Biotechnol. 2025 Mar;43(3): 312-322
    Toward single-molecule protein sequencing using nanopores.
    Chunzhe Lu, Andrea Bonini, Jakob H Viel, Giovanni Maglia.
      Over the past three decades, biological nanopore sequencing has grown from a research curiosity to a mature technology to sequence nucleic acids at the single-molecule level. Now, recent achievements suggest that nanopores might be able to sequence proteins soon. In this Perspective, we analyze the different approaches that have been proposed to measure proteins and peptides using nanopores. We predict that, more likely than not, nanopores will be capable of identifying full-length proteins at the single-molecule level and with single-amino acid resolution, paving the way to single-molecule protein sequencing. This would allow several applications in proteomics that are at present challenging, including measuring the heterogeneity of post-translational modifications, quantifying low-abundance proteins and characterizing protein splicing.
    DOI:  https://doi.org/10.1038/s41587-025-02587-y
  8. Cell Syst. 2025 Mar 19. pii: S2405-4712(25)00068-7. [Epub ahead of print]16(3): 101235
    SPARROW reveals microenvironment-zone-specific cell states in healthy and diseased tissues.
    Peiyao A Zhao, Ruoxin Li, Temi Adewunmi, Jessica Garber, Claire Gustafson, June Kim, Jocelin Malone, Adam Savage, Peter Skene, Xiao-Jun Li.
      Spatially resolved transcriptomics technologies have advanced our understanding of cellular characteristics within tissue contexts. However, current analytical tools often treat cell-type inference and cellular neighborhood identification as separate and hard clustering processes, limiting comparability across scales and samples. SPARROW addresses these challenges by jointly learning latent embeddings and soft clusterings of cell types and cellular organization. It outperformed state-of-the-art methods in cell-type inference and microenvironment zone delineation and uncovered zone-specific cell states in human and mouse tissues that competing methods missed. By integrating spatially resolved transcriptomics and single-cell RNA sequencing (scRNA-seq) data in a shared latent space, SPARROW achieves single-cell spatial resolution and whole-transcriptome coverage, enabling the discovery of both established and unknown microenvironment zone-specific ligand-receptor interactions in the human tonsil. Overall, SPARROW is a computational framework that provides a comprehensive characterization of tissue features across scales, samples, and conditions.
    Keywords:  cell neighborhood; computational biology; immunology; spatial transcriptomics; tissue biology
    DOI:  https://doi.org/10.1016/j.cels.2025.101235
  9. Front Cell Dev Biol. 2025 ;13 1559183
    Epigenetic regulation of reprogramming and pluripotency: insights from histone modifications and their implications for cancer stem cell therapies.
    Woori Bae, Eun A Ra, Myon Hee Lee.
      Pluripotent stem cells (PSCs) possess the extraordinary capability to differentiate into a variety of cell types. This capability is tightly regulated by epigenetic mechanisms, particularly histone modifications. Moreover, the reprogramming of somatic or fate-committed cells into induced pluripotent stem cells (iPSCs) largely relies on these modifications, such as histone methylation and acetylation of histones. While extensive research has been conducted utilizing mouse models, the significance of histone modifications in human iPSCs is gaining increasing recognition. Recent studies underscore the importance of epigenetic regulators in both the reprogramming process and the regulation of cancer stem cells (CSCs), which are pivotal in tumor initiation and the development of treatment resistance. This review elucidates the dynamic alterations in histone modifications that impact reprogramming and emphasizes the necessity for a balance between activating and repressive marks. These epigenetic marks are influenced by enzymes such as DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). Furthermore, this review explores therapeutic strategies aimed at targeting these epigenetic modifications to enhance treatment efficacy in cancer while advancing the understanding of pluripotency and reprogramming. Despite promising developments in the creation of inhibitors for histone-modifying enzymes, challenges such as selectivity and therapy resistance continue to pose significant hurdles. Therefore, future endeavors must prioritize biomarker-driven approaches and gene-editing technologies to optimize the efficacy of epigenetic therapies.
    Keywords:  cancer stem cells; epigenetic regulations; histone modifications; pluripotent stem cells (PSCs); reprogramming
    DOI:  https://doi.org/10.3389/fcell.2025.1559183
  10. PLoS Biol. 2025 Mar;23(3): e3003052
    The end of the genetic paradigm of cancer.
    Sui Huang, Ana M Soto, Carlos Sonnenschein.
      Genome sequencing of cancer and normal tissues, alongside single-cell transcriptomics, continues to produce findings that challenge the idea that cancer is a 'genetic disease', as posited by the somatic mutation theory (SMT). In this prevailing paradigm, tumorigenesis is caused by cancer-driving somatic mutations and clonal expansion. However, results from tumor sequencing, motivated by the genetic paradigm itself, create apparent 'paradoxes' that are not conducive to a pure SMT. But beyond genetic causation, the new results lend credence to old ideas from organismal biology. To resolve inconsistencies between the genetic paradigm of cancer and biological reality, we must complement deep sequencing with deep thinking: embrace formal theory and historicity of biological entities, and (re)consider non-genetic plasticity of cells and tissues. In this Essay, we discuss the concepts of cell state dynamics and tissue fields that emerge from the collective action of genes and of cells in their morphogenetic context, respectively, and how they help explain inconsistencies in the data in the context of SMT.
    DOI:  https://doi.org/10.1371/journal.pbio.3003052
  11. Genome Res. 2025 Mar 20.
    Unraveling the hidden complexity of cancer through long-read sequencing.
    Qiuhui Li, Ayse G Keskus, Justin Wagner, Michal B Izydorczyk, Winston Timp, Fritz J Sedlazeck, Alison P Klein, Justin M Zook, Mikhail Kolmogorov, Michael C Schatz.
      Cancer is fundamentally a disease of the genome, characterized by extensive genomic, transcriptomic, and epigenomic alterations. Most current studies predominantly use short-read sequencing, gene panels, or microarrays to explore these alterations; however, these technologies can systematically miss or misrepresent certain types of alterations, especially structural variants, complex rearrangements, and alterations within repetitive regions. Long-read sequencing is rapidly emerging as a transformative technology for cancer research by providing a comprehensive view across the genome, transcriptome, and epigenome, including the ability to detect alterations that previous technologies have overlooked. In this review, we explore the current applications of long-read sequencing for both germline and somatic cancer analysis. We provide an overview of the computational methodologies tailored to long-read data and highlight key discoveries and resources within cancer genomics that were previously inaccessible with prior technologies. We also address future opportunities and persistent challenges, including the experimental and computational requirements needed to scale to larger sample sizes, the hurdles in sequencing and analyzing complex cancer genomes, and opportunities for leveraging machine learning and artificial intelligence technologies for cancer informatics. We further discuss how the telomere-to-telomere genome and the emerging human pangenome could enhance the resolution of cancer genome analysis, potentially revolutionizing early detection and disease monitoring in patients. Finally, we outline strategies for transitioning long-read sequencing from research applications to routine clinical practice.
    DOI:  https://doi.org/10.1101/gr.280041.124
  12. Nature. 2025 Mar 19.
    Mutations that accrue through life set the stage for stomach cancer.
    Callum Oddy, Marnix Jansen.
      
    Keywords:  Cancer; DNA sequencing; Genetics; Genomics
    DOI:  https://doi.org/10.1038/d41586-025-00803-y
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