Investigating the Antioxidant Role of Lipoprotein Uptake in Kidney Cancer

Abstract
Clear cell renal cell carcinomas (ccRCC), the most common type of kidney cancer, rewire their metabolism to
avidly take up circulating lipids carried by lipoproteins. However, the precise contributions of these lipids to cancer
progression remain unclear. We recently demonstrated that ccRCC tumors bolster their antioxidant defenses by
increasing their uptake of lipoproteins, which carry most circulating lipids. This enhanced lipoprotein uptake
confers resistance to lipid peroxidation and subsequent ferroptotic cell death. Both major lipoprotein classes,
low-density lipoproteins (LDL) and high-density lipoproteins (HDL), exhibit anti-ferroptotic properties; however,
HDL has a much stronger antioxidant effect than LDL. Blocking the uptake of these antioxidant-rich lipoproteins
induces oxidative stress and suppresses tumor growth. Despite these findings, the specific lipid functional nodes
by which lipoproteins influence the redox state of ccRCC cells, and the distinct contributions of different
lipoprotein classes to this phenomenon, remain uncertain.
My research aims to investigate the antioxidant role of lipoprotein uptake in ccRCC by systematically examining
their influence on tumor metabolism and progression. First, I will identify the antioxidant components of
lipoproteins in ccRCC tumors. Using focused analytical and functional genetic approaches, I will pinpoint the lipid
cargo acquired from lipoprotein uptake and assess its impact on the antioxidant response of ccRCCs in vitro and
in vivo. Second, I will dissect the relative contribution of individual lipoprotein classes to ccRCC tumor growth.
By employing genetic manipulation of class-specific uptake mechanisms, I will determine the unique effects of
each lipoprotein class on the antioxidant response of ccRCC tumors in vivo. Finally, I aim to elucidate the
mechanism underlying the strong antioxidant effect of HDL in cancer. Through a systematic analysis of lipidomic,
proteomic, and genetic changes in response to HDL versus LDL uptake, I will clarify the differing anti-ferroptotic
effects of these two lipoprotein classes. This research builds on our previous work by providing a mechanistic
understanding of lipoprotein-mediated antioxidant protection and delineating the roles of different lipoprotein
classes in this process.
Tumors evade oxidative damage and other metabolic challenges by uptaking antioxidant-rich lipoproteins. This
proposal seeks to explore this crucial antioxidant function in ccRCC. By systematically analyzing the
contributions of lipoprotein classes to tumor redox homeostasis, we aim to identify targeted therapeutic strategies
to improve outcomes for patients with aggressive ccRCC.

Grant Number: 1F31CA310232-01
NIH Institute/Center: NIH
Principal Investigator: Dylan Calhoon