bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–10–05
thirteen papers selected by
Xiao Qin, University of Oxford
  1. Spatially resolving cancer: from cell states to therapy.
  2. Dissecting the impact of transcription factor dose on cell reprogramming heterogeneity using scTF-seq.
  3. Sequencing-free whole-genome spatial transcriptomics at single-molecule resolution.
  4. Lmo3-expressing peri-isthmus progenitor cells sustain renewal and repair of the mammalian intestinal telocyte niche.
  5. Colorectal cancer molecular profiling: Opportunities for early detection.
  6. High-depth Whole Genome Sequencing of Single Human Colon Crypts Uncovers New View on Crypt Clonality.
  7. Beyond the scope: an update on colon cancer screening tests.
  8. Deciphering the Tumor Microenvironment Composition Using Bulk Transcriptomics: A Guide to Recent Advances and Open Challenges.
  9. Dietary cysteine enhances intestinal stemness via CD8+ T cell-derived IL-22.
  10. Fast and furious: mapping epithelial cellular turnover into intestinal transcriptomic atlases.
  11. Perturb-seq reveals distinct responses to pluripotency regulator dosages underlying the control of self-renewal and differentiation.
  12. A scientist's guide to AI agents - how could they help your research?
  13. Contractile fibroblasts form a transient niche for the branching mammary epithelium.
  1. Trends Cancer. 2025 Oct 02. pii: S2405-8033(25)00230-4. [Epub ahead of print]
    Spatially resolving cancer: from cell states to therapy.
    Guangsheng Pei, Yang Liu, Linghua Wang.
      Recent advances in spatial multi-omics technologies and analytical methods are transforming our understanding of how cancer cells and their microenvironments interact to drive critical processes such as lineage plasticity, immune evasion, and therapeutic resistance. By linking cancer cell states, lineage plasticity, clonal dynamics, oncogenic pathways, and cellular interactions to their spatial context, these innovations provide deep biological insights and reveal clinically relevant molecular programs and spatial biomarkers. This review highlights key breakthroughs in spatial profiling and computational approaches, including integration with computational pathology, multimodal data, and machine learning to uncover important biological insights. We discuss challenges in spatial multimodal data integration and emerging clinical applications, and we propose a roadmap to accelerate clinical translation and advance precision oncology through spatially resolved, actionable, molecular insights.
    Keywords:  cancer cell state; computational pathology; machine learning; multimodal data integration; spatial multi-omics; spatial profiling
    DOI:  https://doi.org/10.1016/j.trecan.2025.09.002
  2. Nat Genet. 2025 Oct 03.
    Dissecting the impact of transcription factor dose on cell reprogramming heterogeneity using scTF-seq.
    Wangjie Liu, Wouter Saelens, Pernille Rainer, Marjan Biočanin, Vincent Gardeux, Antoni Jakub Gralak, Guido van Mierlo, Angelika Gebhart, Julie Russeil, Tingdang Liu, Wanze Chen, Bart Deplancke.
      Reprogramming often yields heterogeneous cell fates, yet the underlying mechanisms remain poorly understood. To address this, we developed single-cell transcription factor sequencing (scTF-seq), a single-cell technique that induces barcoded, doxycycline-inducible TF overexpression and quantifies TF dose-dependent transcriptomic changes. Applied to mouse embryonic multipotent stromal cells, scTF-seq generated a gain-of-function atlas for 384 mouse TFs, identifying key regulators of lineage specification, cell cycle control and their interplay. Leveraging single-cell resolution, we uncovered how TF dose shapes reprogramming heterogeneity, revealing both dose-dependent and stochastic cell state transitions. We classified TFs into low-capacity and high-capacity groups, with the latter further subdivided by dose sensitivity. Combinatorial scTF-seq demonstrated that TF interactions can shift from synergistic to antagonistic depending on the relative dose. Altogether, scTF-seq enables the dissection of TF function, dose and cell fate control, providing a high-resolution framework to understand and predict reprogramming outcomes, advancing gene regulation research and the design of cell engineering strategies.
    DOI:  https://doi.org/10.1038/s41588-025-02343-7
  3. Cell. 2025 Oct 01. pii: S0092-8674(25)01037-2. [Epub ahead of print]
    Sequencing-free whole-genome spatial transcriptomics at single-molecule resolution.
    Yubao Cheng, Shengyuan Dang, Yuan Zhang, Yanbo Chen, Ruihuan Yu, Miao Liu, Shengyan Jin, Ailin Han, Samuel Katz, Siyuan Wang.
      Recent breakthroughs in spatial transcriptomics technologies have enhanced our understanding of diverse cellular identities, spatial organizations, and functions. Yet existing spatial transcriptomics tools are still limited in either transcriptomic coverage or spatial resolution, hindering unbiased, hypothesis-free transcriptomic analyses at high spatial resolution. Here, we develop reverse-padlock amplicon-encoding fluorescence in situ hybridization (RAEFISH), an image-based spatial transcriptomics method with whole-genome coverage and single-molecule resolution in intact tissues. We demonstrate the spatial profiling of transcripts from 23,000 human or 22,000 mouse genes in single cells and tissue sections. Our analyses reveal transcript-specific subcellular localization, cell-type-specific and cell-type-invariant zonation-dependent transcriptomes, and gene programs underlying preferential cell-cell interactions. Finally, we further develop our technology for the direct spatial readout of guide RNAs (gRNAs) in an image-based, high-content CRISPR screen. Overall, these developments offer a broadly applicable technology that enables high-coverage, high-resolution spatial profiling of both long and short, native and engineered RNAs in many biomedical contexts.
    Keywords:  high content CRISPR screen; highly multiplexed RNA imaging; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.cell.2025.09.006
  4. Dev Cell. 2025 Sep 26. pii: S1534-5807(25)00564-7. [Epub ahead of print]
    Lmo3-expressing peri-isthmus progenitor cells sustain renewal and repair of the mammalian intestinal telocyte niche.
    Daxin Jiang, Guoli Zhu, Yongchao Zhang, Jiawen Wang, Nannan Qian, Zhen Jin, Qingyu Sun, Haimeng Yu, Kebei Tang, Tao Cai, Fengchao Wang, Rongwen Xi.
      Intestinal telocytes that reside immediately beneath the intestinal epithelium exert niche-supporting roles for intestinal stem cells and their progenies. They are heterogeneous cells compartmentalized along the crypt-villus axis, but the mechanisms governing the maintenance of this telocyte population remain unclear. Here, we identify a distinct population of subepithelial mesenchymal cells in the developing mouse embryo, marked by LIM Domain Only 3 (Lmo3), as the cellular origin of post-natal intestinal telocytes. The Lmo3+ cells emerge prior to villus formation at embryonic day 13.5, and after birth, they progressively acquire a spatial confinement to the intestinal isthmus region, where they persist as long-lived, slow-cycling cells, supplying both peri-villus and peri-crypt telocytes. Further, we show that Lmo3+ cells respond rapidly to tissue damage, becoming activated to promote repair of the telocyte niche. Therefore, a quiescent and damage-responsive progenitor cell population marked by Lmo3 maintains the intestinal telocyte niche.
    Keywords:  BMP; FOXL1; LMO3; cell differentiation; intestinal telocyte; irradiation damage; mesenchymal cell niche; stem cell self-renewal; telocyte progenitor cell; villus formation
    DOI:  https://doi.org/10.1016/j.devcel.2025.09.004
  5. Clin Transl Med. 2025 Oct;15(10): e70474
    Colorectal cancer molecular profiling: Opportunities for early detection.
    Alexandra Sala, Lisa van den Driest, Nicholas J W Rattray, Caroline H Johnson, James M Cameron, Sajid A Khan, David S Palmer, Matthew J Baker.
      Colorectal cancer (CRC) is one of the most common and deadliest cancers worldwide, and incidence rates are rising. However, early detection and intervention can improve the survival rates and quality of life of affected patients. Current screening tests used to streamline patients into colonoscopy either lack test adherence or sensitivity for detecting premalignant and early-stage CRC, reducing the advantages of screening measures. Cost-effective and minimally invasive diagnostic tests which can detect immune system and metabolic changes are key to lower the incidence of CRC advanced stages. We herein discuss the statistics, risk factors and unique genetic characteristics of CRC, focussing on the importance of understanding non tumour-derived information in premalignant states for developing comprehensive techniques to achieve earlier diagnosis of CRC. Moreover, the advantages and limitations of current UK and USA screening programmes and emerging detection tools are discussed, along with prospective diagnostics such as genomics, proteomics and spectroscopy.
    Keywords:  CRC; cancer; colorectal; detection; diagnostics; early‐onset; early‐stage; liquid biopsy
    DOI:  https://doi.org/10.1002/ctm2.70474
  6. bioRxiv. 2025 Sep 26. pii: 2025.09.24.677335. [Epub ahead of print]
    High-depth Whole Genome Sequencing of Single Human Colon Crypts Uncovers New View on Crypt Clonality.
    Zarko Manojlovic, Cindy Okitsu, Timothy Okitsu, Jordan Wlodarczyk, Michael R Lieber, Yong Hwee Eddie Loh, Chih-Lin Hsieh.
      It is generally accepted that each colon crypt is monoclonal and is populated by a single stem cell lineage after early human life. It has been impossible to profile somatic mutations genome-wide because high-depth and high-quality whole genome sequencing (WGS) of single cells is unachievable without tissue culture or whole genome amplification (WGA). Therefore, the cell-to-cell heterogeneity in each individual remains mostly unknown. Applying our novel WGA-free WGS method to obtain >30X post-alignment depth, we comprehensively profiled somatic mutations in 71 single human colon crypts with matched bulk controls from 14 individuals. Analysis reveals that colon crypts are commonly of multiple lineages in human adults. Our study is the first to demonstrate that an appropriately designed WGS approach can determine cell- to-cell heterogeneity in natural cell clones. The much higher sensitivity of WGS than the previous methods in lineage tracing can unlock the complex stem cell dynamics in the colon crypt.
    DOI:  https://doi.org/10.1101/2025.09.24.677335
  7. Curr Opin Gastroenterol. 2025 Sep 25.
    Beyond the scope: an update on colon cancer screening tests.
    Timothy Yen, Minh Do, Swati G Patel.
       PURPOSE OF REVIEW: Colorectal cancer (CRC) is common and rising among persons under age 50, but screening uptake is sub-optimal, particularly in 45-49 year-olds. Death from CRC can be prevented through detection and removal of advanced precancerous colorectal lesions (APLS) or detection of CRC at an early stage. In this review, we cover average-risk CRC screening options and present a framework for test selection in different clinical settings.
    RECENT FINDINGS: The optimal CRC screening test should be highly sensitive for APLs and early stage CRC, easy to access, affordable to patient and payers, and appropriate for screening settings. Organized screening is administered systematically on the population-level, while opportunistic screening relies on individual provider-patient shared decision making. In addition to established options such as fecal immunochemical testing, multitarget stool DNA testing, and colonoscopy, novel options include stool-based RNA testing, next-generation stool-based DNA testing, and blood-based DNA testing. Although blood-based tests may be convenient, their low sensitivity for APLs can unintentionally lead to negative consequences for CRC prevention.
    SUMMARY: Uptake, cost, and efficacy of established and novel CRC screening tests influence the modality of choice for specific screening settings. Colonoscopy and stool-based tests should generally be first-line for CRC screening.
    Keywords:  colorectal cancer screening; stool DNA; stool RNA
    DOI:  https://doi.org/10.1097/MOG.0000000000001138
  8. Methods Mol Biol. 2026 ;2959 233-252
    Deciphering the Tumor Microenvironment Composition Using Bulk Transcriptomics: A Guide to Recent Advances and Open Challenges.
    Sotiris Ouzounis, Donya Zojaji, Sandra García-Mulero, Marco Barreca, Paolo Gandellini, Theodora Katsila, Rebeca Sanz-Pamplona, Maurizio Callari.
      Tumors are complex ecosystems comprising diverse cell types actively participating to carcinogenesis, tumor progression, and treatment response. Understanding the tumor microenvironment (TME) dynamics has become of primary importance, especially with the increasing clinical implementation of immunotherapy. Low and high-throughput single cell and spatial technologies are providing high-resolution strategies for the study of the tumor ecosystem. However, their cost and complexity limit widespread use. Bulk transcriptomics has become a widely used strategy to obtain the expression profile of large cohorts of tumors or preclinical models. Several methods implementing a deconvolution analysis have been developed to estimate from bulk transcriptomics the prevalence of multiple cell types to reconstruct the tumor ecosystem composition.In this chapter, we introduce deconvolution analysis, the main steps, the recent advancements, and open challenges. Our emphasis lies on robust benchmarking methodologies, highlighting the importance of clear parameter definition and appropriate metric selection for reliable results across different software tools.Using CIBERSORTx and BayesPrism, we conduct a practical analysis on triple-negative breast cancer (TNBC) datasets from The Cancer Genome Atlas (TCGA) dataset. We illustrate the impact of various factors such as preprocessing methods, reference datasets, and software choice on deconvolution outcomes.Integrating insights from benchmarking analyses and real-world applications, we provide guidance to optimize and control for the quality of deconvolution analysis, weighting both its potential and limitations. Deconvolution analysis can contribute to unravelling the complexities of the tumor microenvironment, but further research is needed to enhance accuracy and reproducibility.
    Keywords:  Bulk; Cancer; Cell type; Challenges; Deconvolution; Immune; Microenvironment; TME; Transcriptomics
    DOI:  https://doi.org/10.1007/978-1-0716-4734-9_16
  9. Nature. 2025 Oct 01.
    Dietary cysteine enhances intestinal stemness via CD8+ T cell-derived IL-22.
    Fangtao Chi, Qiming Zhang, Jessica E S Shay, Shixun Han, Johanna Ten Hoeve, Yin Yuan, Zhenning Yang, Heaji Shin, Samuel Block, Sumeet Solanki, Yatrik M Shah, Matthew G Vander Heiden, Judith Agudo, Ömer H Yilmaz.
      A fundamental question in physiology is understanding how tissues adapt and alter their cellular composition in response to dietary cues1-8. The mammalian small intestine is maintained by rapidly renewing LGR5+ intestinal stem cells (ISCs) that respond to macronutrient changes such as fasting regimens and obesogenic diets, yet how specific amino acids control ISC function during homeostasis and injury remains unclear. Here we demonstrate that dietary cysteine, a semi-essential amino acid, enhances ISC-mediated intestinal regeneration following injury. Cysteine contributes to coenzyme A (CoA) biosynthesis in intestinal epithelial cells, which promotes expansion of intraepithelial CD8αβ+ T cells and their production of interleukin-22 (IL-22). This enhanced IL-22 signalling directly augments ISC reparative capacity after injury. The mechanistic involvement of the pathway in driving the effects of cysteine is demonstrated by several findings: CoA supplementation recapitulates cysteine effects, epithelial-specific loss of the cystine transporter SLC7A11 blocks the response, and mice with CD8αβ+ T cells lacking IL-22 or a depletion of CD8αβ+ T cells fail to show enhanced regeneration despite cysteine treatment. These findings highlight how coupled cysteine metabolism between ISCs and CD8+ T cells augments intestinal stemness, providing a dietary approach that exploits ISC and immune cell crosstalk for ameliorating intestinal damage.
    DOI:  https://doi.org/10.1038/s41586-025-09589-5
  10. Mol Syst Biol. 2025 Oct 02.
    Fast and furious: mapping epithelial cellular turnover into intestinal transcriptomic atlases.
    Christoph Kilian, Lorenz Adlung.
      
    DOI:  https://doi.org/10.1038/s44320-025-00156-8
  11. bioRxiv. 2025 Aug 07. pii: 2025.08.07.669196. [Epub ahead of print]
    Perturb-seq reveals distinct responses to pluripotency regulator dosages underlying the control of self-renewal and differentiation.
    Jielin Yan, Hyein S Cho, Renhe Luo, Michael A Beer, Wei Li, Danwei Huangfu.
      Precise regulation of transcription factor (TF) expression is critical for maintaining cell identity, but studies on how graded expression levels affect cellular phenotypes are limited. To address this gap, we employed human embryonic stem cells (hESCs) as a dynamic model to study gene dosage effects and systematically titrated key TFs NANOG and OCT4 expression using CRISPR interference (CRISPRi). We then profiled transcriptomic changes in hESCs under self-renewal and differentiation conditions using single-cell RNA-seq (scRNA-seq). Quantitative modeling of these Perturb-seq datasets uncovers distinct response patterns for different types of genes, including a striking non-monotonic response of lineage-specific genes during differentiation, indicating that mild perturbations of hESC TFs promote differentiation while strong perturbations compromise it. These discoveries suggest that fine-tuning the dosage of stem cell TFs can enhance differentiation efficiency and underscore the importance of characterizing TF function across a gradient of expression levels.
    DOI:  https://doi.org/10.1101/2025.08.07.669196
  12. Nature. 2025 Oct 03.
    A scientist's guide to AI agents - how could they help your research?
    Elizabeth Gibney.
      
    Keywords:  Machine learning
    DOI:  https://doi.org/10.1038/d41586-025-03246-7
  13. Nat Commun. 2025 Sep 29. 16(1): 8576
    Contractile fibroblasts form a transient niche for the branching mammary epithelium.
    Jakub Sumbal, Robin P Journot, Kriti Attri, Veronika Danek, Candice Merle, Marisa M Faraldo, Zuzana Sumbalova Koledova, Silvia Fre.
      Fibroblasts are stromal cells found in connective tissue that are critical for organ development, tissue homeostasis and pathology. Single-cell transcriptomic analyses have revealed a high level of inter- and intra-organ heterogeneity of fibroblasts. However, the functional implications and lineage relations of different fibroblast subtypes remained unexplored, especially in the mammary gland. Here, we provide a comprehensive characterization of pubertal mouse mammary fibroblasts, through single-cell RNA sequencing, spatial mapping, functional assays, and in vivo lineage tracing. We unravel a transient niche-forming population of specialized contractile fibroblasts that exclusively localize around the tips of the growing mammary epithelium and are recruited from preadipocytes in the surrounding fat pad stroma. Using organoid-fibroblast co-cultures we reveal that different fibroblast populations can acquire contractile features when in direct contact with the epithelium, promoting organoid branching. The detailed in vivo characterization of these specialized cells and their lineage history provides insights into fibroblast heterogeneity and implicates their importance for creating a signalling niche during mouse mammary gland development.
    DOI:  https://doi.org/10.1038/s41467-025-63612-x
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