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) genesignaling dysregulation in clear cell renal cell carcinoma (ccRCC) tumorigenesis. The objective of the project is to introduce Vhlgene loss into the FeNTA mouse model of kidney cancer, and to perform other assays in human cells/tissues, in order to testthe central hypothesis that cellular iron accumulation cooperates with Vhl loss to promote ccRCC tumorigenesis. Specific aimsof this proposal are to: 1) determine how Vhl genetic loss alters the incidence, latency and histology of iron-induced mouseccRCC tumorigenesis; 2) determine how Vhl genetic loss alters the genomic and immunologic landscape of iron-induced murineRCC tumors, including relative to the human ccRCC landscape; and 3) determine the role of the Vhl protein target, HIF-2, ininducing iron dependency of Vhl-inactivated ccRCC cells. A key feature of this project is the novel introduction of Vhl loss into acarcinogenic animal model of RCC, which for the first time will allow in vivo study of molecular and cellular ccRCC phenotypesthat are induced by Vhl loss, including genomic and immunologic effects. Current progress on Aim 1 includes completion in allmice of iron treatments, renal MRI scanning, and kidney/tumor tissue harvest. Work on Aim 2 to characterize the genomic andimmumologic landscape of these tumors will be completed in the next half year. Work on Aim 3 is mostly completed and suggeststhat iron-dependency of VHL-inactivated ccRCC cells is independent of HIF-2 overexpression. These findings collectivelysupport a HIF-2-independent synergistic interplay between VHL dysregulation and iron dysregulation in ccRC

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Document Details

Document Type
Technical Report
Publication Date
Sep 01, 2023
Accession Number
AD1217438

Entities

People

  • Eric Kauffman

Organizations

  • Roswell Park Comprehensive Cancer Center

Tags

DTIC Thesaurus Topics

  • Abstracts
  • Apoptosis
  • Biological Staining And Labeling
  • Cell Line
  • Cell Physiological Processes
  • Cells
  • Computational Biology
  • Cyanides
  • Genes
  • Genetic Phenomena
  • Genetic Structures
  • Genetics
  • Histopathology
  • Kidney Cancer
  • Lymphocytes
  • Medical Personnel
  • Procurement

Fields of Study

  • Biology

Readers

  • Materials Science and Engineering.
  • Molecular and Cellular Biology
  • Neurological Diseases/Conditions/Disorders

Technology Areas

  • Biotechnology
  • Biotechnology - Cancer Biotech