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.

项目总结/文摘