bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–09–27
sixteen papers selected by
Xiao Qin, University of Oxford
  1. Human Small Intestinal Organoids Differentiation Protocols Towards All Mature Epithelial Lineages.
  2. From blunt-force treatment to precision: 25 years of transformation in cancer research.
  3. Tutorial: interrogating biology using organoid technologies.
  4. Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer.
  5. In vivo intercellular CRISPR screens using viral proximity barcoding reveal regulators of tumor-immune interactions.
  6. Stroma-Dominant Colorectal Cancer Harbors CAF-Rich Spatial Architecture and EMT-Associated Cancer Cell Plasticity Detectable After Dissemination.
  7. Intestinal Organoids Culture in Synthetic Hydrogels.
  8. An integrated spatially defined roadmap of normal and cancer-associated colon fibroblasts.
  9. Daily briefing: How to turn a paper into an AI agent.
  10. The Epigenetic Aging-Cancer Continuum: Biomarkers, Metabolism, and Therapy.
  11. Not 'cold' but conditional: emerging principles of immunotherapy in colorectal cancer.
  12. Bridging the Precancerous Gap in Colorectal Cancer Through AI-Enhanced Liquid Biopsy, Endoscopy, and Digital Pathology.
  13. AI co-scientists are revolutionizing how research is done.
  14. Understanding and targeting the tumour matrisome.
  15. Single-cell analysis of chromatin accessibility in the human intestine identifies regulatory programs and clarifies genetic associations in Crohn's disease.
  16. Updated Protocols for 3D and 2D Culture and Histological Analysis of Intestinal Organoids.
  1. Methods Mol Biol. 2027 ;3059 149-165
    Human Small Intestinal Organoids Differentiation Protocols Towards All Mature Epithelial Lineages.
    Adriana Martinez-Silgado, Lulu Huang, Joep Beumer, Hans Clevers.
      The small intestine plays a crucial role in nutrient uptake and metabolism regulation while maintaining a barrier that protects against the harsh environment of the lumen. These different tasks are carried out by a multitude of cell types, continuously generated by the resident stem cell population, and whose specification is under tight regulatory control. Organoids are self-organizing 3D structures derived from tissue-resident stem cells, which retain the ability to differentiate into all other epithelial lineages. Protocols to enrich for the various cell subtypes in the intestine have greatly advanced in recent years. Here, we provide an updated overview of these protocols, which direct human small intestinal organoids differentiation into various mature cell lineages, recapitulating the in vivo gut.
    Keywords:  Adult stem cell-derived organoids; Differentiation; Epithelial lineages; Human small intestine
    DOI:  https://doi.org/10.1007/978-1-0716-5412-5_11
  2. Nat Rev Cancer. 2026 Oct;26(10): 739-740
    From blunt-force treatment to precision: 25 years of transformation in cancer research.
      
    DOI:  https://doi.org/10.1038/s41568-026-00980-6
  3. Nat Protoc. 2026 Sep 24.
    Tutorial: interrogating biology using organoid technologies.
    Jeroen M Bugter, Simon T Schafer, Roland Rad.
      Organoids provide a versatile platform for studying fundamental biology, complementing traditional cell culture and in vivo models. Their unique features, such as self-organization and the possibility for their precise manipulation, have enabled key discoveries in tissue homeostasis, development and disease. This tutorial presents an overview of organoid technologies and protocols across a broad spectrum of applications, from investigating cell fate decisions and cell-cell or cell-microbe interactions to the study of genetic diseases, species evolution and translational/clinical questions. By focusing on adult stem cell-derived intestinal and human pluripotent stem cell-derived brain organoids, we highlight models with distinct characteristics that together reflect the broader spectrum of organoid systems, tissue types and research contexts. For applications not supported by these models, we discuss organoids derived from other tissues. We also outline current challenges in the field and highlight emerging innovations that are promising to shape future directions.
    DOI:  https://doi.org/10.1038/s41596-026-01447-6
  4. Science. 2026 Sep 24. 393(6818): eaeg4791
    Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer.
    Clemens Hinterleitner, Valentin J A Barthet, Hailey V Goldberg, Kristen C Vogt, Ana Marie Perea, Logan R Hillger, Stephen Ruiz, Domhnall McHugh, Yu-Jui Ho, Almudena Chaves-Perez, Maria Skamagki, Sara Flowers, Hannah C Styers, Natasha Rekhtman, Xueqian Zhuang, Gabriel Dessotti Barretto, Xiang Li, Jadae T Watson, Wei Luan, Janelle Simon, Tuomas Tammela, Rui Gardner, Charles M Rudin, Paul B Romesser, Matthew J Bott, Aveline Filliol, Daniel A Heller, Scott W Lowe.
      Fibrotic remodeling of tissues and tumors establishes immunosuppressive microenvironments that drive organ dysfunction and, in cancer, limit response to immunotherapy. Senescent-like cells are conserved drivers of fibrosis and therapeutic targets, yet their functional heterogeneity complicates therapeutic intervention. Here, we show that P-selectin is expressed by a subset of senescent-like cells in fibrotic tissues and tumors. Leveraging fucoidan-based nanoparticles that bind P-selectin, we developed senescence-modulating nanoparticles (SMNPs) to selectively target these disease-associated states. SMNPs exerted potent antifibrotic and immunomodulatory effects while improving the therapeutic index. Mechanistically, we identified a pathogenic, immunosuppressive macrophage population as a functional target in vivo. In fibrotic tumors, niche remodeling restored immune infiltration and sensitized tumors to immune checkpoint-based therapies. These findings establish SMNPs as a generalizable strategy to target pathogenic senescent cell subsets across fibrosis and cancer.
    DOI:  https://doi.org/10.1126/science.aeg4791
  5. bioRxiv. 2026 Sep 18. pii: 2026.09.16.752238. [Epub ahead of print]
    In vivo intercellular CRISPR screens using viral proximity barcoding reveal regulators of tumor-immune interactions.
    Peter Du, Seth Kohno, Mengchen Wang, Michael Papanicolaou, Alun Vaughan-Jackson, Leighton Daigh, Qiangwei Peng, Kaitlyn Spees, Aaron McCormick, Markus Diehl, Lacramioara Bintu, Xiaojie Qiu, Ansuman Satpathy, Michael Bassik.
      Cell-cell interactions shape tumor growth, immune evasion, and therapeutic response, but systematically dissecting their genetic regulators in vivo remains challenging. Existing cell-cell interaction tracing technologies rely largely on protein labels or enzymatic reactions, limiting their information content and scalability. To overcome these limitations, we developed match-seq, an imaging-free, sequencing-based cell proximity tracing system that uses virus-like particles to transmit barcodes between neighboring cells. Barcoded mRNAs are transmitted from sender cells to nearby receiver cells, thereby establishing a spatial linkage that can be computationally reconstructed by barcode sequencing after tissue dissociation. We apply this system to an in vivo syngeneic murine tumor model, where we observe robust labeling of all immune cell lineages, and leverage barcode labeling to reconstruct cell type niches that recapitulate known tumor spatial biology. Furthermore, we couple this system with CRISPR perturbations and single-cell RNA sequencing to perform genetic screens in vivo on tumor-immune interactions at single-cell resolution. We use this method to infer cell-cell spatial relationships and uncover genetic dependencies in cancer cells that change the composition and cell state of their local microenvironments. By calculating a local immune activation signature, we are able to prioritize targets whose deletion enhances anti-tumor immunity through distinct effector cell types: loss of Tgfb1 engages CD8 T cells and macrophages, Traf7 loss elicits a CD4 T cell response, and Nectin3 loss promotes NK cell-mediated immunity, relationships that we validate by in vivo immune cell depletion. Notably, Tgfb1 and Nectin3 deletion had little effect on cancer cell fitness in the pooled screen yet suppressed tumor growth when deleted throughout the tumor, demonstrating the potential of match-seq to reveal functionally important tumor-immune interactions that would otherwise remain hidden. Together, these results establish a general framework for pooled genetic dissection of cell-cell interactions in vivo, extending CRISPR screening from cell-intrinsic phenotypes to the mechanisms by which cells shape and respond to their local microenvironments.
    DOI:  https://doi.org/10.64898/2026.09.16.752238
  6. Biomolecules. 2026 Aug 31. pii: 1261. [Epub ahead of print]16(9):
    Stroma-Dominant Colorectal Cancer Harbors CAF-Rich Spatial Architecture and EMT-Associated Cancer Cell Plasticity Detectable After Dissemination.
    Shuji Kitagawa, Naoki Mimura, Hironobu Kambara, Masaaki Hori, Erina Yamanishi, Ayako Ogo, Tatsushi Shiomi, Kazuhiko Yoshimatsu, Tomio Ueno, Shuya Yano.
      Colorectal cancers (CRCs) include stroma-dominant tumors with desmoplasia and differentiated, gland-forming tumors with little stroma. We asked whether this difference reflects stromal abundance alone or also involves a distinct cancer cell state. HEST-1K sections were classified as M-type (stroma-dominant; five patient/tissue units) or D-type (differentiated and cancer cell-dominant; seven units). Prespecified EMT/pEMT, ECM/integrin, YAP/TAZ-TEAD, and DTP/persister gene sets were examined across spatial, bulk, and single-cell datasets and patient-derived malignant ascites cultures. M-type tumors contained broader CAF-rich compartments and higher activity of all four programs in EPCAM/KRT-high regions, including epithelial-dense tumor cores. Activity was greatest near CAF-rich areas. In GSE39582, EMT/pEMT, ECM/integrin, DTP/persister, and invasive epithelial programs were independently associated with recurrence. Ascites-derived cultures from stroma-dominant tumors showed higher ECM/integrin and survival programs. Independent institutional analyses supported the public data findings: focused real-time PCR showed higher MAPK/TGF-beta-related gene expression in M-type-derived than in D-type-derived ascites cells, and IHC showed stronger epithelial CD44v6 expression in M-type primary tumors and metastatic lymph node lesions. CAF co-culture increased VIM-promoter activity. These findings characterize stroma-dominant CRC as a spatially organized ecosystem in which a CAF-rich compartment is associated with stress-adapted cancer cell programs. Its poor prognosis may therefore involve not only stromal abundance but also a morphology-associated cancer cell state detectable after dissemination.
    Keywords:  CMS4; H&E morphology; cancer-associated fibroblast; colorectal cancer; epithelial–mesenchymal transition; malignant ascites; retained epithelial features; spatial transcriptomics
    DOI:  https://doi.org/10.3390/biom16091261
  7. Methods Mol Biol. 2027 ;3059 189-199
    Intestinal Organoids Culture in Synthetic Hydrogels.
    Magda Martinez-Espuga, Alvaro Mata, Paloma Ordóñez-Morán.
      Derived from adult intestinal stem cells, organoids form intricate three-dimensional structures that closely mimic the cellular diversity and spatial organization of the human gut epithelium. Patient-derived organoids (PDOs) can recapitulate patient-specific tumor heterogeneity, making them highly valuable for colorectal cancer research and personalized medicine. However, their long-term in vitro culture still depends mainly on animal-derived materials (e.g., Matrigel) with undefined composition, batch variability, and limited tunability. To overcome these limitations, we introduced the use of synthetic peptide-based hydrogels, particularly peptide amphiphiles alone and in combination with extracellular matrix macromolecules, as a reproducible and tunable alternative. Here, we present a protocol for embedding PDOs in synthetic peptide-based hydrogels, and describe how to extract their RNA for transcriptomic analysis. This workflow enables the culture of intestinal PDOs in synthetic peptide-based hydrogels in a reproducible way, preserving key proliferation and differentiation lineage markers characteristic of PDOs.
    Keywords:  3D; Colorectal cancer; Differentiation; Intestine; Matrigel; Organoids; Synthetic peptide-based hydrogels
    DOI:  https://doi.org/10.1007/978-1-0716-5412-5_14
  8. Mol Syst Biol. 2026 Sep 23.
    An integrated spatially defined roadmap of normal and cancer-associated colon fibroblasts.
    Emma W Viitala, Ella Salminen, Mitro Miihkinen, Toni T Lemmetyinen, Myriam Sévigny, Kiisla K Porvari, Tanisha Malpani, Niki Chalkidi, Athanasia Stavropoulou, Pekka J Päivinen, Tuomas Kaprio, Jaana Hagström, Caj Haglund, Tomi P Mäkelä, Pekka Katajisto, Tero Aittokallio, Vasiliki Koliaraki, Saara Ollila.
      Cancer-associated fibroblasts (CAFs) promote tumorigenesis and represent potential therapeutic targets, highlighting the need for precise understanding of CAF heterogeneity. In colorectal cancer (CRC), CAF subsets and nomenclature vary widely, and many studies overlook the diversity of normal colon fibroblasts that shapes tumor mesenchyme. Here, we combine large-scale single-cell RNA-sequencing analysis with spatial validation and functional assays to construct a comprehensive reference map of human normal colon fibroblasts and mesenchymal subsets, guided by the well-characterized mouse colon. We define three major fibroblast populations, subepithelial myofibroblasts (SEMFs), mucosa-associated fibroblasts (MAFs), and submucosa-associated fibroblasts (SAFs), and characterize a previously underexplored muscle-embedded interstitial fibroblast (MIF) population. This reference enabled mapping of CRC-specific changes, revealing four cancer-specific CAF subsets, including inflammatory CAFs (iCAFs), matrix CAFs (mCAFs), and two precursor populations (pre-CAFs). We also identify robust CRC CAF markers including CTHRC1, infer transcriptional regulators, and define distinct developmental trajectories driving iCAF and mCAF activation. Together, our study provides a spatially and transcriptionally resolved reference map of fibroblasts in the normal colon and CRC, enabling mechanistic studies and informing CAF-targeted therapies.
    DOI:  https://doi.org/10.1038/s44320-026-00247-0
  9. Nature. 2026 Sep 18.
    Daily briefing: How to turn a paper into an AI agent.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-026-02994-4
  10. Genes (Basel). 2026 Sep 16. pii: 1130. [Epub ahead of print]17(9):
    The Epigenetic Aging-Cancer Continuum: Biomarkers, Metabolism, and Therapy.
    Christos Papaneophytou, Myrtani Pieri, Maria-Eleni Makreli, Evelina Charidemou, Eleni P Andreou.
      Aging and cancer form a biological continuum influenced by epigenomic changes, metabolic dysfunction, inflammation, cellular senescence, and loss of tissue homeostasis. Age-related epigenetic alterations can promote cancer, which exploits plasticity for evolution, immune evasion, metastasis, and resistance. Nutrition and metabolism affect this process through one-carbon metabolism, methyl-donor availability, acetyl-CoA and NAD+ balance, redox status, microbiome metabolites, and chromatin enzyme activity. Circulating biomarkers such as cell-free DNA methylation, mutation-based ctDNA, fragmentomic features, and non-coding RNAs can detect tumor and host changes linked to aging, inflammation, nutrition, and treatment with minimal invasiveness. This review explores the epigenetic aging-cancer link, how nutrition and metabolism modify pathways, and the potential of circulating biomarkers for diagnosis, prognosis, prediction, and monitoring. The focus is on epigenetic plasticity, drug-tolerant states, resistance, epigenetic drugs, metabolic targeting, and nutritional interventions. New technologies, including single-cell and spatial epigenomics, long-read sequencing, and multimodal computational approaches, aid biomarker discovery and clinical use. Challenges include variability, misclassification, heterogeneity, confounding, reverse causality, overfitting, and limited validation. Clinical applications need standard workflows, representative cohorts, transparent models, and proof that biomarker-guided strategies improve outcomes.
    Keywords:  cancer; circulating biomarkers; epigenetic aging; metabolism; nutrition; therapeutic response
    DOI:  https://doi.org/10.3390/genes17091130
  11. Trends Cancer. 2026 Sep 21. pii: S2405-8033(26)00206-2. [Epub ahead of print]
    Not 'cold' but conditional: emerging principles of immunotherapy in colorectal cancer.
    Evan R Beiter, Christopher T Chen.
      Repeated Phase 3 failures have framed proficient mismatch repair/microsatellite stable colorectal cancer as 'cold' and immunotherapy-resistant. We argue that this resistance is conditional, shaped by disease stage, metastatic anatomy, spatial immune architecture, and therapeutic mechanism. Recognizing these principles can guide patient selection, biomarker stratification, and drug development to realize immunotherapy's clinical potential.
    Keywords:  colorectal cancer; immunotherapy; microsatellite stable
    DOI:  https://doi.org/10.1016/j.trecan.2026.08.010
  12. Cancers (Basel). 2026 Sep 10. pii: 2940. [Epub ahead of print]18(18):
    Bridging the Precancerous Gap in Colorectal Cancer Through AI-Enhanced Liquid Biopsy, Endoscopy, and Digital Pathology.
    Georgios Saridakis, Dimitrios Mavroudis, John Souglakos.
      Colorectal cancer remains a leading cause of cancer-related mortality despite a prolonged and preventable precancerous phase. This review examines how artificial intelligence and emerging biomarkers may narrow the persistent gap between detecting established cancer and identifying advanced precursor lesions. Blood-based assays integrating cell-free DNA methylation, mutations, fragmentomic patterns, and other analytes achieve encouraging sensitivity for invasive colorectal cancer but remain substantially less sensitive for advanced adenomas and sessile serrated lesions, particularly in prospective average-risk populations. Machine-learning methods can integrate complementary molecular signals, although many models remain limited by case-control designs, spectrum bias, and inadequate external validation. Computer-aided detection increases adenoma detection and reduces miss rates, but benefits for advanced neoplasia, serrated lesions, colorectal cancer incidence, and mortality remain uncertain. AI-augmented digital pathology may improve polyp classification, dysplasia grading, invasive carcinoma recognition, and case prioritization after lesion removal. The greatest clinical value of these technologies is likely to arise from coordinated use within a multimodal, risk-adapted pathway that expands screening participation, prioritizes colonoscopy for individuals at greatest risk, and preserves high-quality colonoscopy and polypectomy as the central preventive intervention.
    Keywords:  artificial intelligence; colorectal cancer; computer-aided detection; digital pathology; liquid biopsy; precancerous lesions; risk-stratified screening
    DOI:  https://doi.org/10.3390/cancers18182940
  13. Nature. 2026 Sep;657(8133): 1108-1110
    AI co-scientists are revolutionizing how research is done.
    Elie Dolgin.
      
    Keywords:  Drug discovery; Machine learning; Technology
    DOI:  https://doi.org/10.1038/d41586-026-02931-5
  14. Nat Rev Clin Oncol. 2026 Sep 21.
    Understanding and targeting the tumour matrisome.
    Dharma Pally, Johanna I Englund, Alexandra Naba.
      The extracellular matrix (ECM) is a dynamic meshwork of proteins and glycans that provides architectural support to cells. This meshwork also conveys mechanical and biochemical signals that orchestrate many cellular processes, including proliferation, survival and migration. ECM accumulation is a hallmark of cancers and correlates with tumour aggressiveness and survival across cancer types. Because of its abundance and accessibility, the ECM constitutes an appealing reservoir of potential biomarkers and therapeutic targets. Yet, early attempts to target the ECM in patients with cancer have failed to provide clinical benefit. Over the past few years, the development of novel proteomic and imaging methods, together with advances in our knowledge of ECM biology provided by fundamental research, have transformed our understanding of the roles of the ECM in tumour progression. In this Review, we describe novel technologies developed to define the composition, physical and mechanical properties, and signalling functions of the ECM and provide an overview of ECM-dependent mechanisms regulating tumour progression. We then illustrate how the ECM is being leveraged to devise prognostic or diagnostic clinical tests. Lastly, we discuss strategies to target the ECM for clinical benefit by using the ECM for the targeted delivery of therapeutic payloads, normalizing the tumour ECM through matritherapies or modulating ECM signalling pathways.
    DOI:  https://doi.org/10.1038/s41571-026-01203-5
  15. Nat Genet. 2026 Sep 25.
    Single-cell analysis of chromatin accessibility in the human intestine identifies regulatory programs and clarifies genetic associations in Crohn's disease.
    Yu Zhao, Ran Zhou, Zepeng Mu, Peter Carbonetto, Xiaoyuan Zhong, Bingqing Xie, Kaixuan Luo, Zhiwei Jiang, Jianqiao Liu, Candace M Cham, Jason Koval, Xin He, Andrew W Dahl, Xuanyao Liu, Eugene B Chang, Anindita Basu, Sebastian Pott.
      Crohn's disease is a complex inflammatory bowel disease resulting from an interplay of genetic, microbial and environmental factors. Cell-type-specific contributions to Crohn's disease etiology and genetic risk are incompletely understood. Here we built a comprehensive atlas of cell-type-resolved chromatin accessibility comprising 557,310 candidate cis-regulatory elements (cCREs) in terminal ileum and ascending colon from 23 patients with active and inactive Crohn's disease and 16 healthy controls. We identified cell-type-specific, anatomical location-specific and context-specific cCREs and characterized the regulatory programs underlying inflammatory responses in the intestinal mucosa of patients with Crohn's disease. These cell-type-resolved data confirmed that Crohn's disease heritability is primarily enriched in adaptive immune cells, in particular T cells, and in innate immune cells, including neutrophils. Using fine-mapped, noncoding Crohn's disease variants, we identified 30 variants located within cCREs. Our atlas provides a comprehensive resource to study gene-regulatory effects in Crohn's disease and health and highlights the cellular complexity underlying Crohn's disease risk.
    DOI:  https://doi.org/10.1038/s41588-026-02755-z
  16. Methods Mol Biol. 2027 ;3059 125-138
    Updated Protocols for 3D and 2D Culture and Histological Analysis of Intestinal Organoids.
    Hikaru Hanyu, Shinya Sugimoto, Toshiro Sato.
      The intestinal epithelium maintains continuous self-renewal and multi-differentiation capacities through the integrated regulation of multiple signaling pathways, including Wnt, bone morphogenetic protein, epidermal growth factor (EGF), and Notch signaling pathways. Based on this principle, a defined combination of EGF, Noggin, and the Wnt agonist R-spondin has been shown to support long-term expansion of mouse intestinal stem cells and the formation of organoids with indefinite self-renewal and full differentiation capacity. In human intestinal organoid cultures, the addition of small molecule inhibitors targeting p38 and TGF-β pathways facilitated epithelial propagation, while replacement of EGF and a p38 inhibitor with insulin-like growth factor-1 and fibroblast growth factor-2 enabled efficient multilineage differentiation. Recently, the monolayer culture of intestinal organoid has been increasingly used due to its advantages of direct access to the apical membrane and its ability to co-culture with gut microbiota. Here, we summarize our recent technological advances in human intestinal organoid culture and histological analysis, providing updated protocols that will deepen the understanding of intestinal homeostasis and the pathogenesis of intestinal diseases.
    Keywords:  Colon; Formalin fixed paraffin embedded; Human; Immunostaining; Intestinal stem cells; Organoid monolayer; Organoids; Small intestine
    DOI:  https://doi.org/10.1007/978-1-0716-5412-5_9
This page is being maintained by Thomas Krichel. It was last updated on 2026‒10‒30 at 16:35.