Cancer biology & therapy · 2026
Fibroblast-associated TPM2 links cell-matrix remodeling to EMT-Notch signaling and gemcitabine resistance in intrahepatic cholangiocarcinoma.
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Zhu Yingjiao, Qiao Zhibin, Chen Zhuhong, Wu Yahua, Xiao Lirong, Lin Fangyu, Lin Xiaoyan, Wang Xinli
Аннотация
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.
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.