基础医学与临床2026，Vol.46Issue(7)：904-912,9.DOI:10.16352/j.issn.1001-6325.2026.07.0904
基于胆管癌类器官的吉西他滨耐药基因特征构建与验证
Construction and validation of a gemcitabine resistance gene signature based on cholangiocarcinoma organoids
摘要
Abstract
Objective To develop a transcriptional signature of gemcitabine(GEM)resistance using patient-derived organoids(PDOs)from cholangiocarcinoma and to validate its biological consistency and predictive rele-vance.Methods Transcriptomic profiles and drug sensitivity data from four PDOs were collected and analyzed through Hallmark pathway enrichment and pre-ranked GSEA in order to construct a 23-gene resistance signature.The associated pathway patterns were validated in TCGA-CHOL and GSE236894 cohorts,while correlations with drug response metrics were assessed with CCLE and PharmacoDB,complemented by experimental validation in cell models.Results GEM resistance was primarily enriched in cell cycle and E2F target pathways.The 23-gene signature was positively correlated with AUC in PDOs and significantly associated with proliferation markers(e.g.,TOP2A,MKI67)and cell cycle activity in independent cohorts.Database analyses further demonstrated a significant positive correlation between the signature score and GEM AAC_recomputed(ρ=0.149,P＜0.001),with higher scores which indicated a stronger resistance.Experimental findings confirmed that signature-related genes remained expressed in re-sistant cells but were suppressed in sensitive cells.Conclusions This signature provides a robust and biologically in-terpretable indicator of GEM resistance in cholangiocarcinoma,with strong generalizability across datasets.关键词
胆管癌/患者来源类器官/吉西他滨耐药/基因特征/生物信息学分析Key words
cholangiocarcinoma/patient-derived organoids/gemcitabine resistance/gene signature/bioinformatics analysis分类
医药卫生引用本文复制引用
陈子然,黄容,卢艳,李凯,宋伟..基于胆管癌类器官的吉西他滨耐药基因特征构建与验证[J].基础医学与临床,2026,46(7):904-912,9.基金项目
国家重点研发计划(2022YFA0806302) （2022YFA0806302）
国家自然科学基金(32571012) （32571012）
中国医学科学院医学与健康科技创新工程(2025-I2M-TS-03,2025-I2M-XHXX-065) （2025-I2M-TS-03,2025-I2M-XHXX-065）
