肝内胆管癌（ICC）的发病率逐年上升，但生存率却无改善、且治疗手段匮乏，这主要源于对ICC的分子病理机制知之甚少。外显子组测序技术的出现使全面解析癌细胞发生发展的分子基础及其与微环境的互动对话密码成为可能。预实验中对2例ICC外显子测序发现它们存在共同基因改变，包括参与间质交互作用的基因；我们还发现，作为高度纤维化的肿瘤，ICC的肿瘤相关纤维母细胞（TAF）具有独特的促癌表型。本研究以ICC是一种"分子网络疾病"和"微环境疾病"为假设，借助高精度、高通量的外显子组测序，无偏倚的富集ICC癌细胞和微环境TAF的全部基因改变。在此基础上，通过生物信息学分析及体内外实验，首次尝试建立ICC的"癌变相关分子网络模型"、"癌转移相关分子网络模型"，以及"癌细胞?TAF"互动对话的"核心正反馈环路"。有望为ICC的分子靶向治疗和微环境治疗提供有效靶点和实验/理论支持，为提高ICC的临床预后贡献力量。

The annual incidence of Intrahepatic cholangiocarcinoma (ICC) is rising. However, no improvemnts have been made in dealing with the poor survival rate and lack of effective treatment of ICC,owing to that the molecular mechanism underlying the pathogenesis of ICC remains elusive. The advent of exome sequencing technique greatly facilitate the comporehensive analysis of molecular mechanism of tumorigeneis and malignant progression, as well as dissect the key interactions between the cancerous cells and their assciated microenvrionment. In our priliminary study, whole exome sequencing of two ICCs revealed shared genetic variations in the two cases, implcating that idenfication of commen theraputic targets in ICC is feasible. In addition, as a solid tumor characterized by a dense desmoplastic stroma, we found that tumor associated fbroblasts (TAF) in ICC were reprogrammed to a tumor-promoting direction. In our current study, on the basis and hypothesis that ICC is a diease of disrupted molecular network and a diease of tumor microenvrionment, we are aimed to capture the whole genetic variations in ICC cells and TAF using the high throughput exome sequencing technique. Then, though advanced bioinformatic analyses, we will try to establish the molecular signatures or networks associated with the tumorigenesis and metastasis of ICC,as well as identify the key positive feedback loops between ICC cells and TAF. Further, in vitro experiments, in vivo mice models and clinical samples will be used to validate the biological role and clinical relevance of these key molecules in the above signatures, networks and loops. On the accomplisment of this study, the valuable data would provide effective targets for molcular targeted therapy and tumor microenvironment-orientied therapy in ICC, leading to significant improvemnts in patient survial in the near future.