Characterization of a Novel Critical Interplay Between VHL Inactivation and Iron Metabolism in Clear Cell Renal Cell Carcinoma Tumorigenesis
Abstract
This project investigates the interplay between cellular iron accumulation and von Hippel Lindau (Vhl) gene signaling dysregulation in clear cell renal cell carcinoma (ccRCC) tumorigenesis. The objective of the project is to introduce Vhl gene loss into the FeNTA mouse model of kidney cancer, and to perform other assays in human cells/tissues, in order to test the central hypothesis that cellular iron accumulation cooperates with Vhl loss to promote ccRCC tumorigenesis. Specific aims of this proposal are to: 1) determine how Vhl genetic loss alters the incidence, latency and histology of iron-induced mouse ccRCC tumorigenesis; 2) determine how Vhl genetic loss alters the genomic and immunologic landscape of iron induced murine RCC tumors, including relative to the human ccRCC landscape; and 3) determine the role of the Vhl protein target, HIF-2, in inducing iron dependency of Vhl-inactivated ccRCC cells. A key feature of this project is the novel introduction of Vhl loss into a carcinogenic animal model of RCC, which for the first time will allow in vivo study of molecular and cellular ccRCC phenotypes that are induced by Vhl loss, including genomic and immunologic effects. Current progress on Aim 1 includes completion of mouse treatments with iron, however longer follow up is needed to determine the effects on renal tumorigenesis. Work on Aim 2 will be performed in the latter half of the next year after development and harvest of murine tumors. Work on Aim 3 is mostly completed and suggests that iron-dependency of VHL-inactivated ccRCC cells is independent of HIF-2 overexpression. These findings collectively support a HIF-2-independent synergistic interplay between VHL dysregulation and iron dysregulation in ccRCC.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2022
- Accession Number
- AD1191195
Entities
People
- Eric C. Kauffman
Organizations
- Roswell Park Comprehensive Cancer Center