FGFR4 intracellular domain promotes tumor progression in cholangiocarcinoma

项目概要/摘要 该项目的长期目标是改善患者的治疗选择， 胆管癌通过更好地了解驱动疾病的途径， 对治疗的抵抗在世界范围内，肝癌是仅次于肺癌的第二大癌症- 相关死亡。胆管癌是一种发病率逐年上升的原发性肝癌， 有效的治疗选择。目前的项目将调查规范和非规范 成纤维细胞生长因子受体-4（FGFR 4）信号在胆管癌发生中的作用 进展初步数据表明胆管癌细胞表现出自分泌 通过配体FGF 19的表达和分泌的FGFR 4信号传导。抑制这种 途径增加细胞凋亡和减少细胞生长，并在G1/S检查点起作用， S期持续时间和有丝分裂。FGFR 4在肿瘤组织中强表达， 正常的胆管FGFR抑制显著降低大鼠肿瘤大小，并敲低FGFR。 FGFR 4防止皮下肿瘤形成。我们发现了一种新的蛋白水解酶 全长受体的裂解产物，其由胞内结构域（R4- ICD）。R4-ICD含有C-末端酪氨酸激酶结构域，激活AKT，并阻止 凋亡该提议的中心假设是通过FGFR 4和R4-ICD的信号传导 驱动胆管癌的发生、发展和化学抗性。aim 1中的实验 将确定R4-ICD和FGFR 4如何促进恶性特征。目标2将确定 FGFR 4和R4-ICD的肿瘤起始机制。第三个目标将展示 FGFR 4和R4-ICD在化疗耐药中的作用该项目的成功完成将 增加我们对FGFR 4如何促进胆管癌进展的理解， 对治疗的抗性，定义R4-ICD的新生物学，并测试抑制R4-ICD的治疗策略。 FGFR 4加工或激酶活性。

Project summary/Abstract The long-term goal of this project is to improve therapeutic options for patients with cholangiocarcinoma by better understanding the pathways that drive disease and increase resistance to therapy. Worldwide, liver cancer is now second only to lung cancer for cancer- related deaths. Cholangiocarcinoma is a primary liver cancer with rising incidence and few effective treatment options. The current project will investigate canonical and non-canonical fibroblast growth factor receptor-4 (FGFR4) signaling in cholangiocarcinoma initiation and progression. Preliminary data demonstrated that cholangiocarcinoma cells exhibited autocrine FGFR4 signaling through expression and secretion of the ligand FGF19. Inhibition of this pathway increased apoptosis and decreased cell growth with effects at the G1/S checkpoint, S phase duration, and mitosis. FGFR4 is strongly expressed in tumor tissue compared to normal bile ducts. FGFR inhibition markedly reduced tumor size in rats and knockdown of FGFR4 prevented subcutaneous tumor formation. We have identified a novel proteolytic cleavage product of the full-length receptor that is composed of the intracellular domain (R4- ICD). R4-ICD contains the C-terminal tyrosine kinase domain, activated AKT, and prevented apoptosis. The central hypothesis of this proposal is that signaling through FGFR4 and R4-ICD drives cholangiocarcinoma initiation, progression, and chemoresistance. Experiments in aim 1 will determine how malignant features are promoted by R4-ICD and FGFR4. Aim 2 will identify tumor-initiating mechanisms of FGFR4 and R4-ICD. The third aim will demonstrate the role FGFR4 and R4-ICD in chemotherapy resistance. Successful completion of this project will increase our understanding of how FGFR4 promotes cholangiocarcinoma progression and resistance to therapy, define new biology of R4-ICD, and test treatment strategies that inhibit FGFR4 processing or kinase activity.