FGFR4 intracellular domain promotes tumor progression in cholangiocarcinoma

FGFR4胞内结构域促进胆管癌的肿瘤进展

• 批准号: 10316178
• 负责人: Justin L. Mott
• 金额: $ 34.13万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316178
• 关键词: 11q13; Adult; Annual Reports; Apoptosis; Apoptotic; Automobile Driving; Bile Duct Neoplasms; Biliary; Biliary Tract Cancer; Biology; C-terminal; Cell Cycle Progression; Cell Death; Cell Proliferation; Cell Survival; Cell membrane; Cells; Cessation of life; Chemoresistance; Cholangiocarcinoma; Chromosomes; Complementary DNA; Data; Defect; Disease; Effectiveness; Epithelial; Exhibits; FGF19 gene; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Genomic Instability; Goals; Granzyme; Hepatic; Heritability; Human; Incidence; Length; Ligands; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Mediator of activation protein; Mitosis; Mitotic spindle; Modeling; Mus; Mutation; National Cancer Institute; Null Lymphocytes; Pathway interactions; Patients; Phosphotransferases; Play; Primary Malignant Neoplasm of Liver; Process; Production; Proteins; Proto-Oncogene Proteins c-akt; Rattus; Receptor Inhibition; Receptor Signaling; Reporting; Role; S phase; STAT3 gene; Sampling; Signal Transduction; Testing; Therapeutic; Tumor Tissue; Tumor Weights; Tyrosine Kinase Domain; autocrine; base; bile duct; cancer site; cell growth; cell type; chemosensitizing agent; chemotherapy; cholangiocyte; effective therapy; experimental study; fibroblast growth factor receptor 4; gamma secretase; improved; in vivo; intestinal epithelium; knock-down; malignant phenotype; neoplastic cell; novel; prevent; receptor; receptor expression; subcutaneous; targeted treatment; therapeutic target; therapy development; therapy resistant; treatment strategy; tumor; tumor growth; tumor initiation; tumor progression

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.

项目概要/摘要 该项目的长期目标是改善患有以下疾病的患者的治疗选择 通过更好地了解驱动疾病和增加胆管癌的途径 对治疗的抵抗。在世界范围内，肝癌目前是仅次于肺癌的第二大癌症—— 相关死亡。胆管癌是一种原发性肝癌，发病率不断上升，且很少见。 有效的治疗方案。当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 (FGFR4) 信号在胆管癌发生和发展中的作用 进展。初步数据表明胆管癌细胞表现出自分泌 FGFR4 通过配体 FGF19 的表达和分泌进行信号传导。对此的抑制 途径增加细胞凋亡并减少细胞生长，并在 G1/S 检查点产生影响， S期持续时间和有丝分裂。与 FGFR4 相比，FGFR4 在肿瘤组织中强烈表达 正常胆管。 FGFR 抑制显着减小了大鼠的肿瘤大小并敲低了 FGFR4 阻止皮下肿瘤形成。我们发现了一种新型蛋白水解酶 由胞内结构域（R4- ICD）。 R4-ICD 含有 C 端酪氨酸激酶结构域，可激活 AKT，并阻止 细胞凋亡。该提案的中心假设是通过 FGFR4 和 R4-ICD 发出信号 驱动胆管癌的发生、进展和化疗耐药。目标 1 的实验 将决定 R4-ICD 和 FGFR4 如何促进恶性特征。目标 2 将确定 FGFR4 和 R4-ICD 的肿瘤启动机制。第三个目标将展示作用 FGFR4 和 R4-ICD 在化疗耐药中的作用。该项目的顺利完成将 增加我们对 FGFR4 如何促进胆管癌进展的理解 治疗耐药性，定义 R4-ICD 的新生物学，并测试抑制的治疗策略 FGFR4 加工或激酶活性。