Proteomic Analysis of WNT Signaling and Metabolism of Fibrolamellar Hepatocellular Carcinoma

Author

James Knox

Date of Award

2023

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Simon Laboratory

Abstract

Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of liver cancer that primarily affects young adults and adolescents.Although characterized as a subvariant of hepatocellular carcinoma (HCC), we have shown it is distinct based on its pathogenesis, patient population and drug response. Our lab has identified a fusion gene DNAJB1::PRKACA that is found in almost all FLC tumor samples sequenced to date. The fusion gene when expressed in mouse liver is sufficient to generate FLC, and elimination of the fusion transcript kills human tumors. The fusion results from a ~400kb deletion on chromosome 19, beginning after the first exon ofDNAJB1, which encodes for a member of the DnaJ or Hrsp40 family of proteins, and ends before the second exon of PRKACA, the catalytic subunit of protein kinase A (PKAc). To date, there is no known successful treatment for this disease, and the five-year survival rate is around 40%. In this Thesis, I will present my work in investigating several areas in which the disease alters normal cellular pathways. First, I investigate the role Wnt signaling plays in the pathogenesis of FLC. It has long been reported that canonical Wnt signaling may play a role based on the transcriptomic analysis, and synergistic mutagenesis screens. I will next utilize proteomics, imaging, and drug screening data which shows that Canonical Wnt signaling through β-catenin does not play a significant role in FLC. In the following chapter I will show my work on researching the metabolism and molecular dynamics of the mitochondria in FLC.It has long been reported that there is an unusual increase in the number of mitochondria in FLC compared to normal hepatocytes. I use immunofluorescence as well as transcriptomics, proteomics, and phosphoproteomics analysis to investigate some of the ways mitochondria are altered in FLC.

Comments

A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy

Recommended Citation

Knox, James, "Proteomic Analysis of WNT Signaling and Metabolism of Fibrolamellar Hepatocellular Carcinoma" (2023). Student Theses and Dissertations. 763.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/763