bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–09–14
sixteen papers selected by
Xiao Qin, University of Oxford
  1. scTrace+: Enhancing cell fate inference by integrating the lineage-tracing and multi-faceted transcriptomic similarity information.
  2. Taming cancer evolution surprises.
  3. Protocol for multiplexed transcription factor activity detection using optimized barcoded reporters and an automated computational pipeline.
  4. Coupling CRISPR scanning with targeted chromatin accessibility profiling using a double-stranded DNA deaminase.
  5. Spatial multi-omics technologies and applications in cancer.
  6. Deep visual proteomics reveals an in vivo-like phenotype of orthotopically transplanted human colon organoids.
  7. Scvi-hub: an actionable repository for model-driven single-cell analysis.
  8. The multi-kingdom cancer microbiome.
  9. Weighing the benefits of screening for early-onset colorectal cancer.
  10. Defining the mucosal ecosystem: epithelial-mesenchymal interdependence in gastrointestinal health and disease.
  11. Benchmarking genomic language models.
  12. Deciphering regulatory sequence grammar.
  13. AI chatbots are already biasing research - we must establish guidelines for their use now.
  14. Host and microbiome lipid metabolism in colorectal cancer development and therapy.
  15. Risk of colorectal cancer and participation in fecal immunochemical test-based screening.
  16. Unravelling the genetics and epigenetics of the ageing tumour microenvironment in cancer.
  1. Cell Syst. 2025 Sep 03. pii: S2405-4712(25)00231-5. [Epub ahead of print] 101398
    scTrace+: Enhancing cell fate inference by integrating the lineage-tracing and multi-faceted transcriptomic similarity information.
    Wenbo Guo, Zeyu Chen, Xinqi Li, Jingmin Huang, Qifan Hu, Jin Gu.
      Deciphering the cell state dynamics is crucial for understanding biological processes. Single-cell lineage-tracing technologies provide an effective way to track single-cell lineages by heritable DNA barcodes, but the high missing rates of lineage barcodes and the intra-clonal heterogeneity bring great challenges to dissecting the mechanisms of cell fate decision. Here, we systematically evaluate the features of single-cell lineage-tracing data and then develop an algorithm, scTrace+, to enhance the cell dynamic traces by incorporating multi-faceted transcriptomic similarities into lineage relationships via a kernelized probabilistic matrix factorization model. We assess its feasibility and performance by conducting ablation and benchmarking experiments on multiple real datasets and show that scTrace+ can accurately predict the fates of cells. Further, scTrace+ effectively identifies some important driver genes implicated in cellular fate decisions of diverse biological processes, such as cell differentiation or tumor drug responses. A record of this paper's transparent peer review process is included in the supplemental information.
    Keywords:  cell fate inference; data enhancement; single-cell lineage tracing
    DOI:  https://doi.org/10.1016/j.cels.2025.101398
  2. Nat Methods. 2025 Sep 10.
    Taming cancer evolution surprises.
    Vivien Marx.
      
    DOI:  https://doi.org/10.1038/s41592-025-02802-3
  3. STAR Protoc. 2025 Sep 10. pii: S2666-1667(25)00472-1. [Epub ahead of print]6(3): 104066
    Protocol for multiplexed transcription factor activity detection using optimized barcoded reporters and an automated computational pipeline.
    Max Trauernicht, Vinícius H Franceschini-Santos, Hatice Yücel, Bas van Steensel.
      Transcription factors (TFs) regulate the genome in response to signaling events. Detecting their activity is crucial to deciphering the regulatory networks of cells. Here, we present a protocol for multiplexed TF activity detection using a barcoded plasmid library of optimized "prime" TF reporters in cultured cells. We describe steps for library transfection, RNA processing for barcode sequencing, and a computational pipeline for analyzing differential TF activity, enabling high-throughput and quantitative TF profiling. For complete details on the use and execution of this protocol, please refer to Trauernicht et al.1.
    Keywords:  Bioinformatics; Cell Biology; Cell culture; Gene Expression; Genomics; Molecular Biology; RNAseq; Sequence analysis; Sequencing; Systems biology
    DOI:  https://doi.org/10.1016/j.xpro.2025.104066
  4. Nat Methods. 2025 Sep 11.
    Coupling CRISPR scanning with targeted chromatin accessibility profiling using a double-stranded DNA deaminase.
    Heejin Roh, Simon P Shen, Yan Hu, Hui Si Kwok, Allison P Siegenfeld, Ceejay Lee, Marcanthony U Zepeda, Chun-Jie Guo, Shelby A Roseman, Caroline Comenho, Vijay G Sankaran, Jason D Buenrostro, Brian B Liau.
      Genome editing enables sequence-function profiling of endogenous cis-regulatory elements, driving understanding of their mechanisms. However, these approaches lack direct, scalable readouts of chromatin accessibility across long single-molecule chromatin fibers. Here we leverage double-stranded DNA cytidine deaminases to profile chromatin accessibility at endogenous loci of interest through targeted PCR and long-read sequencing, a method we term targeted deaminase-accessible chromatin sequencing (TDAC-seq). With high sequence coverage at targeted loci, TDAC-seq can be integrated with CRISPR perturbations to link genetic edits and their effects on chromatin accessibility on the same single chromatin fiber at single-nucleotide resolution. We employed TDAC-seq to parse CRISPR edits that activate fetal hemoglobin in human CD34+ hematopoietic stem and progenitor cells (HSPCs) during erythroid differentiation as well as in pooled CRISPR and base-editing screens tiling an enhancer controlling the globin locus. We further scaled the method to interrogate 947 variants in a GFI1B-linked enhancer associated with myeloproliferative neoplasm risk in a single pooled CRISPR experiment in CD34+ HSPCs. Together, TDAC-seq enables high-resolution sequence-function mapping of single-molecule chromatin fibers by genome editing.
    DOI:  https://doi.org/10.1038/s41592-025-02811-2
  5. Biosystems. 2025 Sep 09. pii: S0303-2647(25)00186-8. [Epub ahead of print] 105576
    Spatial multi-omics technologies and applications in cancer.
    Lulin Ji.
      Spatial multi-omics integrates individual genomics technologies with a single technology that simultaneously acquires data from multiple genomics, enabling parallel or even identical tissue sections for joint analysis of cells in tissues. It facilitates the analysis of cell-cell-interactions and provides a three-dimensional panoramic view of tissues. Thus, joint profiling of spatial multi-omics features may enable us to reconstruct key processes in tumorigenesis. Through spatial multi-omics technology, researchers have revealed spatial cellular interactions, TLS identification, changes in immune function, and established a spatial map of human tumors and a spatial gene database, which facilitates the development of personalized tumor therapy. In the future, there may be a need to further develop new spatial analysis techniques and tools, mainly in terms of spatial and temporal resolution, throughput, and sensitivity, to aid in cancer diagnosis and treatment and to decode novel mechanisms of tumorigenesis and development. In this review, we provide guidance for selecting appropriate spatial multi-omics techniques by elucidating the advantages and disadvantages of various spatial multi-omics and highlight advances in cancer field of spatial multi-omics technologies.
    Keywords:  Immune; Precise medicine; Spatial metabolomics; Spatial proteomics; Spatial transcriptomics; Tumor
    DOI:  https://doi.org/10.1016/j.biosystems.2025.105576
  6. Cell Syst. 2025 Sep 10. pii: S2405-4712(25)00229-7. [Epub ahead of print] 101396
    Deep visual proteomics reveals an in vivo-like phenotype of orthotopically transplanted human colon organoids.
    Frederik Post, Annika Hausmann, Sonja Kabatnik, Sophia Steigerwald, Alexandra Brand, Ditte L Clement, Jonathan Skov, Kadi Lõhmussaar, Hjalte L Larsen, Martti Maimets, Theresa L Boye, Gabriela Jez, Toshiro Sato, Casper Steenholdt, Florian Rosenberger, Andreas Mund, Ole H Nielsen, Kim B Jensen, Matthias Mann.
      Intestinal epithelial damage predisposes to disorders like inflammatory bowel disease (IBD), with organoid transplantation emerging as a potential treatment. However, it is not known how well organoids recapitulate in vivo intestinal epithelial cells (IECs). We employed deep visual proteomics (DVP), integrating AI-guided cell classification, laser microdissection, and ultra-high-sensitivity proteomics at the single-cell level to generate an in-depth proteome resource of IECs directly isolated from the human colon and organoids. While in vitro organoids display high proliferation and low functional signatures, xenotransplantation induces a remarkable shift toward an in vivo-like phenotype. We recapitulated this transition by modifying culture conditions. Our data provide a comprehensive spatial proteomics resource and validate xenotransplanted organoids as suitable models for studying human IEC behavior with unprecedented molecular detail and demonstrate their clinical potential for patients with IBD and other intestinal disorders. A record of this paper's transparent peer review process is included in the supplemental information.
    Keywords:  IBD; colon; mass spectrometry; organoids; proteomics; spatial proteomics
    DOI:  https://doi.org/10.1016/j.cels.2025.101396
  7. Nat Methods. 2025 Sep 08.
    Scvi-hub: an actionable repository for model-driven single-cell analysis.
    Can Ergen, Valeh Valiollah Pour Amiri, Martin Kim, Ori Kronfeld, Aaron Streets, Adam Gayoso, Nir Yosef.
      The growing availability of single-cell omics datasets presents new opportunities for reuse, while challenges in data transfer, normalization and integration remain a barrier. Here we present scvi-hub: a platform for efficiently sharing and accessing single-cell omics datasets using pretrained probabilistic models. It enables immediate execution of fundamental tasks like visualization, imputation, annotation and deconvolution on new query datasets using state-of-the-art methods, with massively reduced storage and compute requirements. We show that pretrained models support efficient analysis of large references, including the CZI CELLxGENE Discover Census. Scvi-hub is built within the scvi-tools open-source environment and integrated into scverse. Scvi-hub offers a scalable and user-friendly framework for accessing and contributing to a growing ecosystem of ready-to-use models and datasets, thus putting the power of atlas-level analysis at the fingertips of a broad community of users.
    DOI:  https://doi.org/10.1038/s41592-025-02799-9
  8. Nat Microbiol. 2025 Sep 09.
    The multi-kingdom cancer microbiome.
    Anders B Dohlman, Xiangyu Pan, Laurence Zitvogel, Iliyan D Iliev.
      Microbial influence on cancer development and therapeutic response is a growing area of cancer research. Although it is known that microorganisms can colonize certain tissues and contribute to tumour initiation, the use of deep sequencing technologies and computational pipelines has led to reports of multi-kingdom microbial communities in a growing list of cancer types. This has prompted discussions on the role and scope of microbial presence in cancer, while raising the possibility of microbiome-based diagnostic, prognostic and therapeutic tools. However, additional investigation and thorough validation of cancer microbiome findings are required before this translational potential can be realized. Here we provide historical context and a conceptual framework for the so-called cancer microbiome and summarize experimental studies into tumour-associated bacteria, fungi and other microorganisms. We also discuss the current evidence for microbial colonization of tumours and their varied influence on the disease, including recent debates. Finally, we consider outstanding questions and discuss our outlook for the field.
    DOI:  https://doi.org/10.1038/s41564-025-02103-7
  9. Lancet Gastroenterol Hepatol. 2025 Oct;pii: S2468-1253(25)00270-5. [Epub ahead of print]10(10): 871
    Weighing the benefits of screening for early-onset colorectal cancer.
    The Lancet Gastroenterology Hepatology.
      
    DOI:  https://doi.org/10.1016/S2468-1253(25)00270-5
  10. Nat Rev Gastroenterol Hepatol. 2025 Sep 11.
    Defining the mucosal ecosystem: epithelial-mesenchymal interdependence in gastrointestinal health and disease.
    Frances J England, Manqiang Lin, Michael Sigal, Simon J Leedham.
      The crypt-villus architecture of the intestinal mucosa is underpinned by dynamic interactions between distinct populations of epithelial, stromal and immune cells. Although the epithelial compartment has attracted substantial attention, there is a growing appreciation for the critical role of mesenchymal cells in shaping epithelial stem cell function and dictating lineage specification. In this Review, we outline how the epithelial and mesenchymal compartments of the developing gut evolve in a mutually dependent manner to establish dynamic reciprocal signalling gradients that maintain adult tissue homeostasis. We discuss how perturbations to this delicate ecosystem result in rapid adaptive cellular responses that act to restore tissue function. Furthermore, we explore how the intricate nature of cell fate interdependence also renders the mucosa susceptible to pathological disruption. Drawing on the latest studies, we highlight the crosstalk networks between the epithelial and stromal compartments that underlie these processes and consider how these insights are informing future research directions and therapeutic strategies. In doing so, we advocate for a shift away from the conventional epithelial-centric paradigm toward a more integrated framework that considers the full spectrum of intercellular interactions maintaining intestinal tissue integrity and shaping disease progression.
    DOI:  https://doi.org/10.1038/s41575-025-01113-4
  11. Nat Methods. 2025 Sep 10.
    Benchmarking genomic language models.
    Lin Tang.
      
    DOI:  https://doi.org/10.1038/s41592-025-02829-6
  12. Nat Methods. 2025 Sep 10.
    Deciphering regulatory sequence grammar.
    Lei Tang.
      
    DOI:  https://doi.org/10.1038/s41592-025-02827-8
  13. Nature. 2025 Sep;645(8080): 285
    AI chatbots are already biasing research - we must establish guidelines for their use now.
    Zhicheng Lin.
      
    Keywords:  Machine learning; Research management; Scientific community
    DOI:  https://doi.org/10.1038/d41586-025-02810-5
  14. Trends Cancer. 2025 Sep 10. pii: S2405-8033(25)00203-1. [Epub ahead of print]
    Host and microbiome lipid metabolism in colorectal cancer development and therapy.
    Gabriel Medina Evora, Madita Brauer, Elisabeth Letellier.
      Colorectal cancer (CRC) remains one of the most prevalent cancers, with treatment largely dependent on surgery and chemotherapy, underscoring the need for novel or adjunct therapies. Cancer cells reprogram their lipid metabolism to support proliferation, invasiveness, and chemoresistance, making it a promising therapeutic target. Although several inhibitors of lipogenesis, lipases, lipid uptake, and lipid storage are under investigation in CRC, none have yet shown sufficient efficacy. Importantly, the tumor microenvironment (TME) and the microbiome influence CRC lipid metabolism by supplying compensatory lipids and engaging in crosstalk that affects the efficacy of lipid-targeting therapies. This review describes the role of lipids in CRC and explores how the TME and the gut/tumor microbiome may contribute to current challenges in the development of effective lipid-targeting therapies.
    Keywords:  colorectal cancer; diet; inhibitors; lipid metabolism; microbiome; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2025.08.005
  15. Public Health. 2025 Sep 08. pii: S0033-3506(25)00384-1. [Epub ahead of print]248 105938
    Risk of colorectal cancer and participation in fecal immunochemical test-based screening.
    H J van de Schootbrugge-Vandermeer, L de Jonge, M E van Leerdam, A J van Vuuren, E Dekker, M C W Spaander, I D Nagtegaal, F J van Kemenade, I Lansdorp-Vogelaar, E Toes-Zoutendijk.
       OBJECTIVES: Participation rates in fecal immunochemical test (FIT)-based colorectal cancer (CRC) screening differ across socio-demographic subgroups. The largest health gains could be achieved in subgroups with low participation rates and high risk of CRC. We investigated the CRC risk within different socio-demographic subgroups with low participation in the Dutch CRC screening program.
    STUDY DESIGN: Population-based cohort study.
    METHODS: All individuals invited for the Dutch CRC screening program in 2018 and 2019 were included. Data from a previous study, including screening data and demographic characteristics, were augmented with CRC diagnoses in 2018 and 2019. A multivariable logistic regression was used to assess the association between socio-demographic factors and risk of CRC.
    RESULTS: Overall participation was 72.3% and age-adjusted CRC incidence was 30.3 per 10,000 individuals. Males showed lower participation (69.7 %) but had a higher-than-average CRC risk (35.1). The difference in CRC risk between males and females was less pronounced among non-participants (OR: 1.28, 95% CI: 1.20-1.36) than participants (OR: 1.41, 95% CI: 1.35-1.47). Lower income groups also had lower participation (down to 60.0 %) and higher risk of CRC (down to 30.7), but the difference in CRC risk between low-income groups and high-income groups was only significant among participants (OR lowest vs highest quintile: 1.22, 95% CI: 1.14-1.32). Conversely, individuals with a Turkish/Moroccan migration background had lower participation (48.7 %), but their CRC risk was also lower (18.8; OR: 0.54, 95% CI: 0.46-0.63).
    CONCLUSIONS: CRC risk varies significantly between low-participation groups in the Dutch CRC screening program. Interventions should prioritize the most vulnerable groups, considering both participation and risk of CRC.
    Keywords:  Colorectal cancer; Colorectal cancer screening; health inequities
    DOI:  https://doi.org/10.1016/j.puhe.2025.105938
  16. Nat Rev Cancer. 2025 Sep 08.
    Unravelling the genetics and epigenetics of the ageing tumour microenvironment in cancer.
    Hariharan Easwaran, Ashani T Weeraratna.
      Somatic mutations in several genes, including key oncogenes and tumour suppressor genes, are present from early life and can accumulate as an individual ages, indicating that the potential for cancer is present and growing throughout life. However, the risk of developing cancer rises sharply after 50-60 years of age, suggesting that the ability of these mutations to undergo clonal expansion and drive cancer development is dependent on the progressive changes in the epigenome and microenvironment that occur during ageing. Epigenetic changes, including DNA methylation and histone modifications, can drive various hallmarks of ageing in precancerous cells, including induction of senescence, the senescence-associated secretory phenotype, genomic instability and reduction of nuclear integrity, metabolic and inflammatory stress responses, stem cell function and differentiation potential, and redox balance. This can also alter the normal immune and stromal cells in the tissue microenvironment, which cumulatively enhances the effects of cancer driver mutations, ultimately promoting cancer development and progression in aged individuals. Unravelling these mechanisms will provide novel preventive and therapeutic strategies to limit the burden and progression of cancer in aged individuals.
    DOI:  https://doi.org/10.1038/s41568-025-00868-x
This page is being maintained by Thomas Krichel. It was last updated on 2025‒09‒14 at 11:59.