Clear cell renal cell carcinoma (ccRCC) is the most common and malignant subtype of kidney cancer, which carries a poor prognosis due to resistance to conventional chemotherapy and radiotherapy. Two molecular hallmarks of ccRCC are constitutive transcriptional activity of the hypoxia-inducible factor (HIF) proteins and storag of excess neutral lipid species in cytoplasmic lipid droplets. While recent studies have proposed that metabolic reprogramming of glycolytic and lipid anabolic processes are central to ccRCC tumorigenesis, factors imparting a lipogenic quality to these tumors remain incompletely characterized. The overall goal of this proposal is to elucidate mechanisms of regulation and functional roles of PPAR? in promoting ccRCC progression. Our preliminary data suggest that PPAR?, a master regulator of adipogenesis and lipid metabolism, is overexpressed in ccRCC tumors relative to normal kidney tissue and plays a critical role in maintaining viability of ccRCC cell lines. However, the mechanisms by which PPAR? promotes robust growth in ccRCC remain undefined.
In Aim 1, I will test the hypothesis that HIF-1? mediates deregulated lipid metabolism in ccRCC through direct transcriptional activation of PPAR?. I will perform experiments to establish a HIF-1?-PPAR? axis, and characterize downstream changes in lipid metabolism that promote ccRCC progression. Moreover, I propose to identify a comprehensive set of PPAR? target genes in ccRCC through ChIP-seq and microarray experiments.
In Aim 2, I will test the hypothesis that the lipid chaperone FABP6, which is associated with copy number amplification, mRNA overexpression, and nuclear localization in ccRCC tumors, enhances the activity of PPAR?. Previous reports suggest that fatty acid binding proteins (FABPs) can potentiate the activity of nuclear receptors including PPAR?, through delivery of activating ligands. Our preliminary experiments have demonstrated a significant block in proliferation in ccRCC cell lines following FABP6 suppression, yet the pathways FABP6 influence in ccRCC are not well understood. Together, these experiments will reveal how PPAR? is regulated and functions to maintain tumorigenesis in ccRCC. A better understanding of the factors which mediate altered lipid metabolism will lead to the development of novel, targeted therapies against this disease.

Public Health Relevance

Clear cell renal cell carcinoma (ccRCC) is the most common and malignant subtype of kidney cancer, yet is resistant to current standard of care therapies. Through a more detailed understanding of how alterations in lipid metabolism promote ccRCC progression, the experiments outlined in this proposal will identify novel therapeutic targets for this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31CA206381-01
Application #
9126201
Study Section
Special Emphasis Panel (ZRG1-F09A-D (20)L)
Program Officer
Mcneil, Nicole E
Project Start
2016-07-01
Project End
2019-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$43,576
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Sanchez, Danielle J; Steger, David J; Skuli, Nicolas et al. (2018) PPAR? is dispensable for clear cell renal cell carcinoma progression. Mol Metab 14:139-149