# Fibroblast-associated TPM2 links cell-matrix remodeling to EMT-Notch signaling and gemcitabine resistance in intrahepatic cholangiocarcinoma

Article · Zhu Y, Qiao Z, Chen Z, Wu Y, Xiao L, Lin F, Lin X, Wang X

- Archive id: doi:10.1080/15384047.2026.2725344
- Published: 2026-09-21
- Venue: Cancer biology & therapy
- DOI: https://doi.org/10.1080/15384047.2026.2725344
- PMID: 42766730
- PMCID: PMC13596889
- Citations: 0
- Source URL: https://doi.org/10.1080/15384047.2026.2725344
- PDF: https://europepmc.org/articles/PMC13596889/pdf
- Provenance: europepmc

## 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 reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [Organoids & Organ-on-Chip](https://space-kitty.com/topics/organoids)

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