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Archive > Volume 32 Issue 11 > 2025,32(11):1121-1127. DOI:10.3872/j.issn.1007-385X.2025.11.003 Prev Next
Basic Research
Construction of cholangiocarcinoma organoid models and preliminary analysis of heterogeneity in drug response
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Abstract:
[Abstract] Objective: To construct patient-derived organoid (PDO) models of cholangiocarcinoma (CCA) and evaluate their application values in assessing the drug sensitivity to cisplatin and gemcitabine, both as single agents and in combination. Methods: TTumor tissues were collected from four patients with pathologically confirmed cholangiocarcinoma who had not received any prior systematic treatment. PDO models were constructed using matrigel 3D cultures. The consistency of histological morphology and genetic characteristics between PDO and primary tumors was validated by hematoxylin-eosin (H-E) staining, immunohistochemistry (IHC) and whole-exome sequencing (WES). Drug sensitivity of stably passaged PDO was detected using the adenosine triphosphate (ATP) assay, and dose-response curves were used to calculate the half-maximal inhibitory concentration (IC50 ). Synergistic effects were evaluated by calculating the combination index (CI) through the Chou-Talalay method. Results: PDO models for three CCA strains capable of stable subculturing for over seven generations were successfully constructed. H-E staining and IHC results demonstrated high consistency between the PDO models and the primary tumors. WES analysis revealed that the paired PDO retained approximately 78.4% of the genetic variations present in the source tissues. The IC50 values of the three PDO for cisplatin were (277.50 ± 4.056), (9.129 0 ± 1.012), and (115.50 ± 3.034) μmol/L, respectively, while the IC50 values for gemcitabine were (0.581 8 ± 0.020), (0.012 1 ± 0.008), and (0.048 9 ± 0.004) μmol/L, indicating significant inter-individual differences. In the combination therapy experiment, PDO#1 exhibited a significant synergistic effect (CI = 0.116-0.573); PDO#2 showed antagonism at low doses and synergy at moderate doses; PDO#3 displayed antagonism at low doses, synergy at moderate doses, and a return to antagonism at high doses (CI ≈ 1.99 in the highest concentration group). These results indicated that the synergistic effect of the drug combination was strictly confined to a specific dose range. Conclusion: The CCA PDO model faithfully reproduces the morphological and genetic features of the original tumor, and effectively simulates the heterogeneous drug response patterns in patients' tumors, which provides an efficient and reliable platform for selecting and optimizing personalized clinical treatment strategies.
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