{"id":"doi:10.1080/15384047.2026.2725344","kind":"article","title":"Fibroblast-associated TPM2 links cell-matrix remodeling to EMT-Notch signaling and gemcitabine resistance in intrahepatic cholangiocarcinoma","authors":["Zhu Y","Qiao Z","Chen Z","Wu Y","Xiao L","Lin F","Lin X","Wang X"],"author_count":8,"year":2026,"published":"2026-09-21","venue":"Cancer biology & therapy","cited_by":0,"doi":"10.1080/15384047.2026.2725344","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1080/15384047.2026.2725344","archive_url":"https://space-kitty.com/papers/doi:10.1080/15384047.2026.2725344","updated":null,"pmid":"42766730","pmcid":"PMC13596889","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC13596889/pdf","abstract":"Background Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver malignancy with heterogeneous responses to gemcitabine-based chemotherapy. The cellular and microenvironmental programs associated with the gemcitabine response remain incompletely understood. This study aimed to identify tumor microenvironment-associated regulators of gemcitabine response in ICC and evaluate their functional relevance using patient-derived organoids. Methods Four public single-cell RNA sequencing datasets comprising 50,176 cells were integrated with TCGA-based transcriptomic and drug sensitivity analyses. High-dimensional weighted gene co-expression network analysis was used to identify cell type-associated modules. Predicted gemcitabine IC50-related differentially expressed genes were intersected with the fibroblast-associated module genes. Patient-derived ICC organoids were used for gemcitabine sensitivity testing and CRISPR/Cas9-mediated TPM2 knockout validation. Results Single-cell analysis revealed fibroblast enrichment in ICC, and co-expression analysis identified fibroblast-associated modules enriched in extracellular matrix organization and ECM-receptor interaction. Integrated analysis identified TPM2 as a fibroblast-enriched candidate associated with poor prognosis, activation of epithelial-mesenchymal transition, TGF- β and Notch-related pathways, and dynamic cellular state transitions. Patient-derived ICC organoids retained features of matched tumors and showed distinct gemcitabine sensitivities that were broadly consistent with the clinical imaging responses. In a relatively gemcitabine-resistant organoid model, TPM2 knockout enhanced gemcitabine-induced cytotoxicity and suppressed EMT/ECM-related programs and Notch signaling. Conclusions These findings identify TPM2-associated cell-matrix remodeling as a potential contributor to gemcitabine resistance in ICC and support patient-derived organoids as a functional platform for studying therapeutic vulnerabilities.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Fibroblast-associated TPM2 links cell-matrix remodeling to EMT-Notch signaling and gemcitabine resistance in intrahepatic cholangiocarcinoma\" by Zhu Y, Qiao Z, Chen Z et al., https://doi.org/10.1080/15384047.2026.2725344, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"organoids","name":"Organoids & Organ-on-Chip","domain_slug":"biotech"}],"cited_in_dossiers":[]}