DataSheet_2_Characterization of the Estrogen Response Helps to Predict Prognosis and Identify Potential Therapeutic Targets in Cholangiocarcinoma.pdf

Cholangiocarcinoma (CCA) is an aggressive malignancy originating from the epithelium of the bile duct. The prognosis of patients is poor regardless of radical resection and chemoradiotherapy. The current classification and prognostic model of CCA are unable to satisfy the requirements for predicting the clinical outcome and exploring therapeutic targets. Estrogen signaling is involved in diverse cancer types, and it has long been established that CCA could be regulated by estrogen. In our study, estrogen response was identified to be significantly and stably correlated with poor prognosis in CCA. Employing several algorithms, CCA was classified into ES cluster A and B. ES cluster B was mainly composed of patients with fluke infection and overlapped with CCA cluster 1/2, and ES cluster A was mainly composed of patients without fluke infection and overlapped with CCA cluster 3/4. COMT and HSD17B1 were identified to be responsible for the differential estrogen response between ES clusters A and B, and the estrogen response may be correlated with the differentiation and cancer stemness of CCA at the single-cell level. Complement activation and the expression of C3 and C5, which are mainly expressed by CCA cells, were significantly downregulated in ES cluster B. An estrogen response risk score (ESRS) model was constructed to predict the prognosis of CCA, followed by a nomogram integrating ESRS and clinical features. Finally, altered pathways, applicable drugs and sensitivity to chemical drugs were analyzed specific to the estrogen response. In summary, our results provide insights into the role of the estrogen response in CCA progression as well as applicable drugs and potential therapeutic targets in estrogen metabolism, the complement system and ESRS-related pathways.

胆管癌（Cholangiocarcinoma, CCA）是一类起源于胆管上皮的侵袭性恶性肿瘤。无论接受根治性切除术还是放化疗，患者的预后均较差。当前胆管癌的分类体系与预后模型均无法满足预测临床结局、探索治疗靶点的需求。雌激素信号通路参与多种癌症的发生发展，且学界早已证实胆管癌的发生发展可受雌激素调控。本研究发现，雌激素应答与胆管癌患者的不良预后存在显著且稳定的相关性。本研究采用多种算法将胆管癌样本划分为ES簇A与ES簇B：ES簇B主要由吸虫感染患者构成，且与胆管癌簇1/2高度重合；ES簇A主要由未发生吸虫感染的患者构成，且与胆管癌簇3/4高度重合。研究还鉴定出COMT与HSD17B1是导致ES簇A、B间雌激素应答差异的关键基因，且在单细胞水平上，雌激素应答与胆管癌的分化程度及癌症干细胞干性显著相关。ES簇B中，补体激活过程以及主要由胆管癌细胞表达的C3、C5的表达水平均显著下调。本研究构建了雌激素应答风险评分（ESRS）模型以预测胆管癌患者的预后，并进一步整合ESRS与临床特征构建了列线图。最后，本研究针对雌激素应答特征分析了其对应的异常通路、潜在适用药物以及化疗药物敏感性。综上，本研究结果揭示了雌激素应答在胆管癌进展中的作用，并为雌激素代谢、补体系统及ESRS相关通路中的潜在治疗靶点与适用药物提供了理论依据。