Graduation Date

Summer 8-13-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Justin Mott

Abstract

Cholangiocarcinoma is a cancer of cholangiocytes, or epithelial cells lining the biliary tract. It is associated with a poor prognosis and additional therapeutic treatments are needed to help patients affected by this disease. Fibroblast growth factor receptor 4 (FGFR4) is receptor tyrosine kinase that is involved in various physiologic and pathologic processes. TCGA analysis of thirty different tumor types showed the highest FGFR4 mRNA levels in cholangiocarcinoma. At the protein level, FGFR4 was observed in the majority of cholangiocarcinomas screened and, higher levels were associated with a poorer prognosis. FGFR4 is an N-linked glycosylated receptor tyrosine kinase that we show here is modified through a cleavage process called regulated intramembrane proteolysis, where the intracellular kinase domain is released from the plasma membrane. Both glycosylation status and regulated intramembrane proteolysis have been shown to be involved in modifying cancer phenotypes. As such, a multifaceted approach to FGFR4 signaling was taken to look at the role of glycosylation on FGFR4 signaling and processing. Additionally, the regulated intramembrane proteolysis process was studied, and we identified a new form of FGFR4, R4-ICD, with a signaling role in cholangiocarcinoma cells.

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