bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–10–12
sixteen papers selected by
Xiao Qin, University of Oxford
  1. Deciphering single-cell epigenomic language with a foundation model.
  2. Genetic Engineering of Esophageal Organoids: CRISPR-Based Knock-In for Cell Lineage Tracing.
  3. Current and emerging concepts for systemic treatment of metastatic colorectal cancer.
  4. Ultra-sensitive DNA sequencing maps mutations that precede cancer.
  5. Cell tracking with accurate error prediction.
  6. A cellular and spatial atlas of TP53-associated tissue remodeling defines a multicellular tumor ecosystem in lung adenocarcinoma.
  7. Wnt signalling maintains self-renewal of human hepatoblasts without blocking their differentiation.
  8. Retracing tumor evolution.
  9. Top advances of the year: Noninvasive colorectal cancer screening tests.
  10. Somatic mutation and selection at population scale.
  11. Host-pathogen interactions shape human evolution and future pandemics.
  12. Aspirin and recurrence of PI3K-mutated CRC.
  13. The single-cell atlas of colorectal cancer reveals cellular heterogeneity and key molecular features of the tumor immune microenvironment.
  14. Epithelial guardians against cancer: integrating cell competition and extrusion in early tumor control.
  15. SPP1 Drives Colorectal Cancer Liver Metastasis and Immunotherapy Resistance by Stimulating CXCL12 Production in Cancer-Associated Fibroblasts.
  16. Medicine Nobel goes to scientists who revealed secrets of immune system 'regulation'.
  1. Nat Methods. 2025 Oct 10.
    Deciphering single-cell epigenomic language with a foundation model.
      
    DOI:  https://doi.org/10.1038/s41592-025-02851-8
  2. Methods Mol Biol. 2025 Oct 11.
    Genetic Engineering of Esophageal Organoids: CRISPR-Based Knock-In for Cell Lineage Tracing.
    Kyung-Pil Ko, Jae-Il Park.
      Esophageal organoids serve as powerful systems to study epithelial lineage hierarchies and cancer biology. Gene manipulation in these organoids has traditionally involved overexpression or knockout strategies. However, CRISPR-/Cas9-based knock-in (KI) approaches now enable precise cell lineage tracing and live imaging. Here, we describe protocols to generate fluorescent KI organoids from murine esophageal epithelium by tagging Krt13 (BFP) and Sox2 (mNeon). These dual-reporter organoids allow direct monitoring of growth dynamics and differentiation trajectories. We outline CRISPR/Cas9 design, donor construction using homology-independent approaches (CRISPaint), delivery into organoid cells, enrichment and single-clone isolation, and validation by fluorescence. For organoids, homology-directed repair (HDR) can be relatively inefficient to deliver the reporter frame. Thus, we highlight the practical advantages of non-homologous end joining (NHEJ)-based methods, which enable robust, frame-accurate KI with minimal cloning. The methods outlined here can be applied broadly for cell lineage tracing, damage-response studies, and cancer modeling.
    Keywords:  BFP; CRISPR/cas9; Esophageal organoid; Knock-in reporter system; Krt13; Mneon; NHEJ; Non-homologous end joining; Sox2
    DOI:  https://doi.org/10.1007/7651_2025_669
  3. Gut. 2025 Oct 05. pii: gutjnl-2025-335412. [Epub ahead of print]
    Current and emerging concepts for systemic treatment of metastatic colorectal cancer.
    Christoph Steup, Kilian Kennel, Markus F Neurath, Stefan Fichtner-Feigl, Florian Greten.
      Colorectal cancer (CRC) is one of the most common malignant cancers and its incidence is steadily rising particularly in young patients. While screening measures and the widespread availability of surgical treatment have led to an impressive improvement of prognosis within the overall CRC population, patients with metastatic CRC still face 5-year survival rates of around 10-25%. Despite continuous development of new systemic treatment strategies that include cytotoxic chemotherapy and targeted therapy, most patients with metastatic CRC eventually progress. However, a small proportion of patients with mismatch repair-deficient or microsatellite unstable CRC responds exceptionally well to treatment with immune checkpoint inhibitors, thereby proving that CRC is in principle amenable to immunotherapy and showing that long-term disease stabilisation can be achieved even in metastasised stages. However, the reasons for the lack of response to immunotherapy in the vast majority of CRC cases remain to be elucidated. Yet, recent evidence suggests that the tumour stroma, which includes non-immune cells in the colorectal tumour microenvironment, mediates immunosuppressive mechanisms that prevent effective immunotherapy. These findings open new avenues for the development of advanced immunotherapies for CRC. In this review, we summarise major developments in the systemic therapy of CRC within the last couple of decades, provide an overview of emerging and soon-to-be implemented therapeutic strategies and present concepts from clinical and preclinical research to manipulate tumour cells and the tumour stroma to sensitise microsatellite stable colorectal tumours to immunotherapy.
    Keywords:  COLORECTAL CANCER
    DOI:  https://doi.org/10.1136/gutjnl-2025-335412
  4. Nature. 2025 Oct 08.
    Ultra-sensitive DNA sequencing maps mutations that precede cancer.
    Jian Carrot-Zhang.
      
    Keywords:  Cancer; DNA sequencing; Epidemiology; Genetics
    DOI:  https://doi.org/10.1038/d41586-025-02975-z
  5. Nat Methods. 2025 Oct 08.
    Cell tracking with accurate error prediction.
    Max A Betjes, Rutger N U Kok, Sander J Tans, Jeroen S van Zon.
      Cell tracking is an indispensable tool for studying development by time-lapse imaging. However, existing cell trackers cannot assign confidence to predicted tracks, which prohibits fully automated analysis without manual curation. We present a fundamental advance: an algorithm that combines neural networks with statistical physics to determine cell tracks with error probabilities for each step in the track. From these, we can obtain error probabilities for any tracking feature, from cell cycles to lineage trees, that function like P values in data interpretation. Our method, OrganoidTracker 2.0, greatly speeds up tracking analysis by limiting manual curation to rare low-confidence tracking steps. Importantly, it also enables fully automated analysis by retaining only high-confidence track segments, which we demonstrate by analyzing cell cycles and differentiation events at scale for thousands of cells in multiple intestinal organoids. Our approach brings cell dynamics-based organoid screening within reach and enables transparent reporting of cell-tracking results and associated scientific claims.
    DOI:  https://doi.org/10.1038/s41592-025-02845-6
  6. Nat Cancer. 2025 Oct 07.
    A cellular and spatial atlas of TP53-associated tissue remodeling defines a multicellular tumor ecosystem in lung adenocarcinoma.
    William Zhao, Thinh T Nguyen, Atharva Bhagwat, Akhil Kumar, Bruno Giotti, Benjamin Kepecs, Jason L Weirather, Navin R Mahadevan, Asa Segerstolpe, Komal Dolasia, Jamshid Abdul-Ghafar, Naomi R Besson, Stephanie M Jones, Brian Y Soong, Chendi Li, Sebastien Vigneau, Michal Slyper, Isaac Wakiro, Mei-Ju Su, Karla Helvie, Allison Frangieh, Judit Jane-Valbuena, Orr Ashenberg, Mark Awad, Asaf Rotem, Raphael Bueno, Orit Rozenblatt-Rosen, Kathleen Pfaff, Scott Rodig, Aaron N Hata, Aviv Regev, Bruce E Johnson, Alexander M Tsankov.
      Tumor protein p53 (TP53) is the most frequently mutated gene across many cancers and is associated with shorter overall survival in lung adenocarcinoma (LUAD). Here, to define how TP53 mutations affect the LUAD tumor microenvironment (TME), we constructed a multiomic cellular and spatial atlas of 23 treatment-naive human lung tumors. We found that TP53-mutant malignant cells lose alveolar identity and upregulate highly proliferative and entropic gene expression programs consistently across LUAD tumors from resectable clinical samples, genetically engineered mouse models, and cell lines harboring a wide spectrum of TP53 mutations. We further identified a multicellular tumor niche composed of SPP1+ macrophages and collagen-expressing fibroblasts that coincides with hypoxic, prometastatic expression programs in TP53-mutant tumors. Spatially correlated angiostatic and immune checkpoint interactions, including CD274-PDCD1 and PVR-TIGIT, are also enriched in TP53-mutant LUAD tumors and likely engender a more favorable response to checkpoint blockade therapy. Our systematic approach can be used to investigate genotype-associated TMEs in other cancers.
    DOI:  https://doi.org/10.1038/s43018-025-01053-7
  7. Development. 2025 Oct 10. pii: dev.205026. [Epub ahead of print]
    Wnt signalling maintains self-renewal of human hepatoblasts without blocking their differentiation.
    Ekaterini D Zacharis, Carola M Morell, Rute A Tomaz, Arash Shahsavari, Charlotte Grey-Wilson, Maïa Pesic, Vasileios Galanakis, Eleanor C Williams, Irina Mohorianu, Irene Talon, Ludovic Vallier.
      Hepatoblasts play a key role in liver organogenesis by differentiating into hepatocytes and cholangiocytes, the main functional cell types of the liver. Mouse studies have shown the association of Wnt signalling with proliferation and differentiation of hepatoblasts. However, the exact function of this pathway in hepatic development is not fully uncovered, especially in human. Here, we use hepatoblast organoids (HBOs) derived from human foetal livers to investigate the importance of Wnt signalling in self-renewal and cell fate decisions during liver development. We first showed that Wnt plays a key role in hepatoblast self-renewal capacity in vitro by maintaining their proliferative state. However, Wnt was not sufficient to block differentiation of HBOs into hepatocytes or cholangiocytes, suggesting that other factors are necessary to maintain hepatoblast bipotency. Finally, single-cell transcriptomic analyses revealed that Wnt signalling activity correlates with hepatoblast proliferation in the human foetal liver, suggesting that the role for Wnt could be conserved in vivo. Taken together, our results support a model where Wnt signalling acts to preserve the proliferative capacity of hepatoblasts without being sufficient to maintain their bipotent state.
    Keywords:  Cholangiocyte; Hepatoblast; Hepatocyte; Organoid; liver
    DOI:  https://doi.org/10.1242/dev.205026
  8. Nat Methods. 2025 Oct;22(10): 2009
    Retracing tumor evolution.
    Madhura Mukhopadhyay.
      
    DOI:  https://doi.org/10.1038/s41592-025-02876-z
  9. Cancer. 2025 Oct 15. 131(20): e70115
    Top advances of the year: Noninvasive colorectal cancer screening tests.
    Brian Ko, Pakdee Rojanasopondist, William M Grady.
      Colorectal cancer (CRC) screening has been shown to be more effective in preventing deaths from this common cancer, but current methods are suboptimal. Because of limitations and barriers, interval cancers occur, and many people (25%-40%) are not compliant with colorectal cancer screening. Advances over the past year, which have led to a blood-based screening test and more accurate stool tests, address the limitations of current tests. Three clinical trials published in the past year have led to a novel blood-based test, a multitarget stool eRNA test, and an improved multitarget stool DNA test for colorectal cancer screening. The multitarget eRNA stool-based test and multitarget stool DNA test are 94.4% sensitive (87.9% specificity) and 93.5% sensitive (90.6% specificity) for CRC and 45.9% sensitive and 43.4% sensitive for advanced polyps, respectively. The blood test uses cell free DNA to detect CRC and is 83% sensitive for CRC (89.6% specificity) and 13% sensitive for advanced adenomas. These advances provide a novel effective blood-based test for CRC screening, which promises to increase compliance, and more accurate stool-based tests, which promise to lead to fewer interval CRCs.
    Keywords:  cell free DNA; colorectal cancer; prevention; screening; stool test
    DOI:  https://doi.org/10.1002/cncr.70115
  10. Nature. 2025 Oct 08.
    Somatic mutation and selection at population scale.
    Andrew R J Lawson, Federico Abascal, Pantelis A Nicola, Stefanie V Lensing, Amy L Roberts, Georgios Kalantzis, Adrian Baez-Ortega, Natalia Brzozowska, Julia S El-Sayed Moustafa, Dovile Vaitkute, Belma Jakupovic, Ayrun Nessa, Samuel Wadge, Marc F Österdahl, Anna L Paterson, Doris M Rassl, Raul E Alcantara, Laura O'Neill, Sara Widaa, Siobhan Austin-Guest, Matthew D C Neville, Moritz J Przybilla, Wei Cheng, Maria Morra, Lucy Sykes, Matthew Mayho, Nicole Müller-Sienerth, Nicholas Williams, Diana Alexander, Luke M R Harvey, Thomas Clarke, Alex Byrne, Jamie R Blundell, Matthew D Young, Krishnaa T A Mahbubani, Kourosh Saeb-Parsy, Hilary C Martin, Michael R Stratton, Peter J Campbell, Raheleh Rahbari, Kerrin S Small, Iñigo Martincorena.
      As we age, many tissues become colonized by microscopic clones carrying somatic driver mutations1-7. Some of these clones represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding of this phenomenon remains limited due to the challenge of detecting mutations in small clones. Here we introduce a new version of nanorate sequencing (NanoSeq)8, a duplex sequencing method with an error rate lower than five errors per billion base pairs, which is compatible with whole-exome and targeted capture. Deep sequencing of polyclonal samples with single-molecule sensitivity simultaneously profiles large numbers of clones, providing accurate mutation rates, signatures and driver frequencies in any tissue. Applying targeted NanoSeq to 1,042 non-invasive samples of oral epithelium and 371 blood samples from a twin cohort, we report an extremely rich selection landscape, with 46 genes under positive selection in oral epithelium, more than 62,000 driver mutations and evidence of negative selection in essential genes. High-resolution maps of selection across coding and non-coding sites are obtained for many genes: a form of in vivo saturation mutagenesis. Multivariate regression models enable mutational epidemiology studies on how exposures and cancer risk factors, such as age, tobacco or alcohol, alter the acquisition or selection of somatic mutations. Accurate single-molecule sequencing provides a powerful tool to study early carcinogenesis, cancer prevention and the role of somatic mutations in ageing and disease.
    DOI:  https://doi.org/10.1038/s41586-025-09584-w
  11. Nat Rev Genet. 2025 Oct 07.
    Host-pathogen interactions shape human evolution and future pandemics.
    Tzachi Hagai.
      
    DOI:  https://doi.org/10.1038/s41576-025-00902-6
  12. Nat Rev Gastroenterol Hepatol. 2025 Oct 06.
    Aspirin and recurrence of PI3K-mutated CRC.
    Jordan Hindson.
      
    DOI:  https://doi.org/10.1038/s41575-025-01137-w
  13. Cancer Immunol Immunother. 2025 Oct 10. 74(11): 336
    The single-cell atlas of colorectal cancer reveals cellular heterogeneity and key molecular features of the tumor immune microenvironment.
    JunHu Li, ZhiQiang Liu, BoYu Zhang, LiuPing You, YueNan Huang.
       BACKGROUND: Colorectal cancer (CRC) is a highly heterogeneous malignancy, with its tumor immune microenvironment (TIME) playing a crucial role in tumor progression, immune evasion, and treatment response. Despite insights from single-cell technologies, challenges such as small samples and inconsistent annotations have limited a comprehensive understanding. Thus, a large-scale, high-resolution single-cell atlas is needed to fully explore the heterogeneity of CRC TIME and guide personalized treatment.
    METHODS: We analyzed single-cell transcriptomic data from 100 CRC samples (371,223 cells). Immune, stromal, and epithelial cells in the TIME were clustered, annotated, and functionally analyzed. Transcription factor networks were inferred using SCENIC, differentiation states assessed with CytoTRACE, and cell-cell communication analyzed via CellPhoneDB. TIME subtypes were constructed from bulk RNA-seq data, followed by survival analysis. SCRN1 was further validated through in vitro experiments.
    RESULTS: This study presents a comprehensive single-cell CRC atlas, revealing significant heterogeneity in T cells, B cells, myeloid cells, fibroblasts, endothelial cells, and epithelial cells within the TIME. We defined two immune ecological subtypes: subtype 1 (enriched in metabolic and motility pathways with poor prognosis) and subtype 2 (enriched in immune response pathways, with better prognosis and greater immunotherapy potential). High SCRN1 expression in malignant epithelial cells correlated with poor prognosis and metastasis. In vitro experiments confirmed the role of SCRN1 in promoting CRC cell proliferation and migration.
    CONCLUSIONS: This study provides a comprehensive characterization of the CRC TIME, links TIME subtypes to prognosis, and identifies SCRN1 as a potential therapeutic target, offering insights for CRC precision subtyping and immunotherapy strategies.
    Keywords:   SCRN1 ; Colorectal cancer; Epithelial cells; TIME subtype; Tumor immune microenvironment
    DOI:  https://doi.org/10.1007/s00262-025-04173-2
  14. Discov Oncol. 2025 Oct 09. 16(1): 1836
    Epithelial guardians against cancer: integrating cell competition and extrusion in early tumor control.
    Grecia Riofrio-Chung, César Rivera.
      Epithelial tissues maintain homeostasis by employing sophisticated mechanisms to promote clearance of precancerous cells, thus preventing tumorigenesis. Two key processes-cell competition and extrusion-collectively termed epithelial defense against cancer (EDAC), enable normal epithelial cells to outcompete or physically expel transformed counterparts. This review integrates recent advances in EDAC, detailing critical proteins, biomechanical cues, and their interplay with immune surveillance. We quantify cellular proportions essential for EDAC efficacy and examine cancer models, focusing on pancreatic, colorectal, and mammary cancers. By linking molecular mechanisms to clinical potential, we position EDAC as a promising frontier for cancer prevention and therapy.
    Keywords:  Cell competition; Cell extrusion; Epithelial cells; Neoplasms; Tumor suppressor proteins
    DOI:  https://doi.org/10.1007/s12672-025-03519-7
  15. Cancer Res. 2025 Oct 06.
    SPP1 Drives Colorectal Cancer Liver Metastasis and Immunotherapy Resistance by Stimulating CXCL12 Production in Cancer-Associated Fibroblasts.
    Shengde Liu, Zizhen Zhang, Zhenghang Wang, Cheng Liu, Guanghao Liang, Ting Xu, Zhiwei Li, Xiaorui Duan, Gehan Xu, Xujiao Feng, Qin Feng, Qi Wang, Dali Han, Cheng Zhang, Jian Li, Lin Shen.
      Colorectal cancer (CRC) remains a major cause of cancer-related morbidity and mortality globally, with 30%-40% of cases developing metastasis, mainly to the liver. Although immunotherapy has shown promise for CRC treatment, patients with CRC liver metastasis (CRLM) experience limited therapeutic benefits, potentially because of an immunosuppressive tumor microenvironment (TME). Thus, an urgent need exists to identify the key players that drive CRLM and potentiate immunotherapeutic resistance. Herein, we established liver metastatic cells through continuous passaging in vivo, allowing the screening of RNA expression profiles related to CRLM. A combination of spatial transcriptomic sequencing and single-cell analysis revealed a substantial upregulation of SPP1 expression and secretion in CRLM. SPP1 induced immunotherapeutic resistance by stimulating CXCL12 production by cancer-associated fibroblasts (CAFs) through activation of β-catenin/HIF-1α-related transcription. CXCL12 promoted epithelial-mesenchymal transition of CRC cells but suppressed CD8+ T cell infiltration. Treatment with a CXCL12 receptor antagonist or anti-SPP1 antibody markedly activated intratumoral CD8+ T cell infiltration and enhanced the efficacy of anti-PD-1 antibody treatment. Elevated SPP1 and CXCL12 corresponded to immunotherapy resistance in CRLM patients. Together, this study highlights the potential of the SPP1/CXCL12 axis as a target and a biomarker for precise cancer immunotherapy in CRLM. The intricate interactions within the TME offer promising avenues for improving therapeutic outcomes in CRC patients with liver metastasis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4916
  16. Nature. 2025 Oct 06.
    Medicine Nobel goes to scientists who revealed secrets of immune system 'regulation'.
    Miryam Naddaf, Elizabeth Gibney.
      
    Keywords:  Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-03193-3
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