bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–07–26
nine papers selected by
Xiao Qin, University of Oxford
  1. Single-cell multimodal profiling of pan-cancer cell lines uncovers gene regulatory principles underlying intrinsic cell states and environmental features.
  2. Spatial biology in cancer epigenetics.
  3. Background genetics and new mutations interact to direct cancer evolution.
  4. Flexible and high-throughput simultaneous profiling of gene expression and chromatin accessibility in single cells.
  5. Genetic background sets the trajectory of experimental cancer evolution.
  6. Bizarre CRISPR enzyme kills cancer cells by shredding their DNA.
  7. Mapping mesenchymal diversity in the human small intestine and organoids.
  8. Single-nucleus multimodal spatial transcriptomics reveals spatial colocalization of neoantigen-expressing tumor cells and cognate T cells.
  9. Towards liquid biopsy-based analysis of antitumour immunity.
  1. Nat Commun. 2026 Jul 23. pii: 6975. [Epub ahead of print]17(1):
    Single-cell multimodal profiling of pan-cancer cell lines uncovers gene regulatory principles underlying intrinsic cell states and environmental features.
    Zihan Xu, Aileen Ugurbil, Joshua Kwan, Chloe Schaefer, Abdulraouf Abdulraouf, Ziyu Lu, Erting Tang, Wei Zhou, Junyue Cao.
      Cancer arises from genetic and epigenetic alterations that reshape chromatin, transcriptional regulation, and malignant cell states. To chart cancer-intrinsic regulatory programs, we build a pan-cancer single-cell atlas of 60 cancer cell lines spanning 16 tissue origins and 20 cancer types, comprising 240,957 snRNA-seq and 223,347 snATAC-seq profiles. Integrative analyses reveal cell-state heterogeneity, core gene-regulatory networks, and a conserved EMT axis transcending tissue of origin; copy-number analysis identifies transcription factor amplification and hyperactivation as drivers of state reprogramming. Comparing cutaneous melanoma with acral melanoma, a rare subtype underrepresented in previous studies, uncovers a universal inflammation-suppressive program in acral and an inflamed landscape in cutaneous melanoma, with JAK-STAT activity as the central discriminator. Integrating data across models and patient cohorts links tumor-intrinsic regulation to microenvironmental composition and therapeutic response. By profiling rare alongside common subtypes, this atlas offers a resource for mapping pan-cancer and subtype-specific regulatory programs shaping cell-state plasticity.
    DOI:  https://doi.org/10.1038/s41467-026-75360-7
  2. Mol Oncol. 2026 Jul 23.
    Spatial biology in cancer epigenetics.
    Eva Crespo-García, Manel Esteller.
      Cancer develops inside organized tissue environments wherein cellular behavior is heavily influenced by local interactions and spatially restricted regulatory programs. While bulk and single-cell sequencing technologies have fundamentally revolutionized our understanding of tumor biology, these techniques often disrupt tissue architecture and therefore fail to capture the spatial context in which molecular processes occur. Spatial transcriptomics has provided important insights into tumor heterogeneity, microenvironmental organization, and cell-to-cell communication. However, gene expression alone offers only an indirect view of the regulatory mechanisms governing cellular states. The emergence of spatial epigenomic technologies now enables the investigation of chromatin accessibility, histone modifications, and DNA methylation while preserving tissue structure. Here, we discuss the current landscape of spatial epigenomics, including spatial ATAC-seq, spatial CUT&Tag, emerging spatial CUT&RUN approaches, spatial DNA methylation profiling, and multimodal strategies integrating epigenetic, transcriptional, and proteomic information within the same tissue context. Despite remaining technical and computational challenges, continued advances are expected to establish spatial epigenomics as a powerful tool for studying cancer pathways and their regulation within intact tissues.
    Keywords:  DNA methylation; cancer; chromatin; epigenetics; histone modifications; spatial biology
    DOI:  https://doi.org/10.1002/1878-0261.70310
  3. Nature. 2026 Jul 22.
    Background genetics and new mutations interact to direct cancer evolution.
      
    Keywords:  Cancer; Genetics; Genomics
    DOI:  https://doi.org/10.1038/d41586-026-02155-7
  4. Elife. 2026 Jul 20. pii: RP110034. [Epub ahead of print]15
    Flexible and high-throughput simultaneous profiling of gene expression and chromatin accessibility in single cells.
    Volker Soltys, Moritz A Peters, Dingwen Su, Marek Kucka, Yingguang Frank Chan.
      Gene regulation underpins development and is an intricate biological process involving transcription, typically at promoters within accessible chromatin. To understand cell-type-specific regulatory networks, the ability to capture both transcription and chromatin accessibility simultaneously is crucial. However, joint measurements are technically challenging and current methodologies still face adoption challenges. Here, we present easySHARE-seq, an improvement on SHARE-seq for the simultaneous measurement of ATAC- and RNA-seq in single cells. We address several limitations of the previous method by improving the barcode and streamlining the protocol. As a result, easySHARE-seq libraries have a usable sequence of up to 300 bp (+200 bp increase), making it suitable for, e.g., investigation of allele-specific signals or variant discovery. Furthermore, easySHARE-seq libraries do not require a dedicated sequencing run thus saving costs. We applied easySHARE-seq to murine liver nuclei and recovered 19,664 nuclei with joint chromatin and expression profiles. By benchmarking against other combinatorial indexing-based techniques, we showed that we can recover over 1.5-fold more transcripts per cell while retaining high scalability and low cost. To showcase our method, we identified cell types, exploited the multiomic measurements to link cis-regulatory elements to their target genes and investigated liver-specific micro-scale changes. We conclude that easySHARE-seq improves upon previous methods and can produce high-quality multiomic datasets. We expect it to be applicable to a wide range of study designs.
    Keywords:  developmental biology; genetics; genomics; hepatocytes; human; liver; liver sinusoidal endothelial cells; mouse
    DOI:  https://doi.org/10.7554/eLife.110034
  5. Nature. 2026 Jul 22.
    Genetic background sets the trajectory of experimental cancer evolution.
    Liver Cancer Evolution Consortium
      Human cancers are heterogeneous1. Dissecting how germline genetic variation and environmental factors shape tumour evolution using human datasets is limited by inherent diversity in genetic backgrounds2 and environmental exposures3-5. Here, to overcome these limitations, we re-ran early tumour evolution hundreds of times in diverged inbred mouse strains, generating matched histology and whole-genome and transcriptome sequences. The sex, environment and carcinogenic exposures were all controlled, and the study design allowed us to capture genetic variation comparable with that observed across human populations while exploiting the nested hierarchical structure of strain-litter-animal-tumour relationships. Our analyses reveal that epistatic interactions between genetic background and acquired somatic mutations result in population-specific disease progression, including choice of driver mutations, occurrence of whole-genome duplication and subclonal selection dynamics that mirror both cancer susceptibility and tumour growth rate. Even modest genetic divergence, comparable with that found across human ancestry groups, can strikingly alter selection pressures during cancer development to shape both cancer risk and the trajectory of tumour evolution.
    DOI:  https://doi.org/10.1038/s41586-026-10821-z
  6. Nature. 2026 Jul 24.
    Bizarre CRISPR enzyme kills cancer cells by shredding their DNA.
    Heidi Ledford.
      
    Keywords:  CRISPR-Cas9 genome editing; Cancer
    DOI:  https://doi.org/10.1038/d41586-026-02268-z
  7. Nat Cell Biol. 2026 Jul 22.
    Mapping mesenchymal diversity in the human small intestine and organoids.
    Kelli F Johnson, Xiangning Dong, Yu-Hwai Tsai, Angeline Wu, Sydney G Clark, Abigail Vallie, Sha Huang, Charlie J Childs, Rachel K Zwick, Ian Glass, Katherine D Walton, Ophir D Klein, Jason R Spence.
      The organization of diverse mesenchymal populations during human small intestinal development is critical for tissue architecture and function yet remains poorly defined. Here, to construct a comprehensive, tissue-scale map of the developing human small intestine at single cell resolution, we leveraged single-cell RNA-sequencing data to build a Xenium spatial transcriptomics gene panel covering the cell diversity of the human small intestine. We defined five subpopulations occupying discrete anatomical locations within the lamina propria and submucosa-the subepithelial cells, lamina propria fibroblasts, submucosal fibroblasts, smooth muscle cells and CXCL13+ fibroblasts. Our data establish molecular markers to distinguish these populations in both sequencing and imaging data. We leverage this high-resolution atlas to interrogate cell-cell signalling, benchmark pluripotent stem cell-derived human intestinal organoids and to demonstrate how this resource can incorporate relative spatial organization into tissue analysis, with broad implications for modelling development, regeneration and disease.
    DOI:  https://doi.org/10.1038/s41556-026-02027-2
  8. Nat Biotechnol. 2026 Jul 22.
    Single-nucleus multimodal spatial transcriptomics reveals spatial colocalization of neoantigen-expressing tumor cells and cognate T cells.
    Adi Nagler, Amit Sud, Jack Y Ghannam, Lucas Pomerance, Camila Robles-Oteiza, Alexander B Afeyan, Jackson A Weir, Andrew J C Russell, Wesley S Lu, McKayla Van Orden, Andrea Sonnenholzner, Giovanni J Marrero, Qiyu Gong, Vipin Kumar, Kun Huang, Chloe Tu, Emma Lin, Bohoon Shim, Gabriel R De Oliveira, MacLean C Sellars, Charles H Yoon, David A Reardon, Toni K Choueiri, Lars R Olsen, Sabina Signoretti, Patrick A Ott, David A Braun, Giacomo Oliveira, Shuqiang Li, Kenneth J Livak, Nir Hacohen, Fei Chen, Catherine J Wu.
      Improved methods to identify therapeutically relevant tumor neoantigens and their cognate T cells would aid the development of precision medicines for cancer. Here, we developed Slide-GoTags, a droplet-based single-nucleus spatial transcriptomics approach that characterizes neoantigen-specific immunity by integrating targeted transcript genotyping and T cell receptor (TCR) sequencing with single-nucleus RNA sequencing from the same slice of frozen tissue. Application of Slide-GoTags to mouse and human tumors revealed colocalization of clonally expanded, neoantigen-specific T cells with tumor cells expressing their cognate neoantigen. We also identified distinct spatial immune landscapes shaped by anti-PD1 or anti-CTLA4 blockade in mouse colorectal tumors. Across human tumor types, Slide-GoTags detected TCR-neoantigen interactions through spatial proximity and identified an enrichment of interferon-driven immunogenicity niches in immunologically 'hot' tumors compared to 'cold' tumors. These niches harbored three T cell clonotypes that colocalized with genotyped neoantigens, highlighting a spatially organized antitumor immune response. Collectively, Slide-GoTags establishes a framework for in situ mapping of T cell-tumor interactions directly from individual tissue.
    DOI:  https://doi.org/10.1038/s41587-026-03194-1
  9. Nat Rev Clin Oncol. 2026 Jul 24.
    Towards liquid biopsy-based analysis of antitumour immunity.
    Klaus Pantel, Doryan Masmoudi, Catherine Alix-Panabières.
      Analysis of tissue biopsy samples is the gold-standard approach to cancer diagnosis and patient selection for biomarker-guided therapies. Although spatial analyses of tumour tissue can provide important insights into local antitumour immune responses, repeated tumour biopsy is invasive and rarely feasible for monitoring dynamic immune responses over time. Technical advances have enabled multimodal analyses of cells and cellular products in peripheral blood samples, which can be obtained easily and repeatedly over the course of the disease. These liquid biopsy-based approaches cannot provide spatial information on the tumour immune microenvironment and tumour-derived material can be highly diluted in the circulation, yet they offer a unique opportunity to monitor systemic immune dynamics, anticipate responses to immunotherapies and detect emerging resistance to treatment. Thus, blood-based analyses might complement tumour tissue analysis. In this Review, we discuss insights on systemic antitumour immune responses that can be gained through the analysis of tumour-derived biomarkers in peripheral blood and/or circulating immune cells.
    DOI:  https://doi.org/10.1038/s41571-026-01181-8
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