Cholesterol auxotrophy as a targetable vulnerability in clear cell renal cell carcinoma

Romain  Riscal; Caroline J Bull; Mattias Johansson; Nicholas John  Timpson; Emma E Vincent; M Celeste  Simon

doi:10.1158/2159-8290.CD-21-0211

Cholesterol auxotrophy as a targetable vulnerability in clear cell renal cell carcinoma

Romain Riscal
, Caroline J Bull
, Mattias Johansson
, Nicholas John Timpson
, Emma E Vincent^*
, M Celeste Simon^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

104 Citations (Scopus)

157 Downloads (Pure)

Abstract

Clear cell renal cell carcinoma (ccRCC) is characterized by large intracellular lipid droplets (LDs) containing free and esterified cholesterol; however, the functional significance of cholesterol accumulation in ccRCC cells is unknown. We demonstrate that, surprisingly, genes encoding cholesterol biosynthetic enzymes are repressed in ccRCC, suggesting a dependency on exogenous cholesterol. Mendelian randomization analyses performed on 31,000 individuals indicate a causal link between elevated circulating high-density lipoprotein (HDL) cholesterol and ccRCC risk. Depriving ccRCC cells of either cholesterol or HDL compromises proliferation and survival in vitro and tumor growth in vivo; in contrast, elevated dietary cholesterol promotes tumor growth. Scavenger Receptor B1 (SCARB1) is uniquely required for cholesterol import, and inhibiting SCARB1 is sufficient to cause ccRCC cell cycle arrest, apoptosis, elevated intracellular reactive oxygen species levels and decreased PI3K/AKT signaling. Collectively, we reveal a cholesterol dependency in ccRCC and implicate SCARB1 as a novel therapeutic target for treating kidney cancer.

Original language	English
Pages (from-to)	3106-3125
Number of pages	20
Journal	Cancer Discovery
Volume	11
Issue number	12
Early online date	8 Jul 2021
DOIs	https://doi.org/10.1158/2159-8290.CD-21-0211
Publication status	Published - Dec 2021

Bibliographical note

Funding Information:
We acknowledge the NIH grants P01CA104838 and R35CA197602 (to M.C. Simon, which support N. Skuli), and Damon Runyon postdoctoral fellowship DRG2326-18 (to R. Riscal). Mendelian randomization and analysis were performed by E.E. Vincent and C.J. Bull supported by Diabetes UK (17/0005587), the Wellcome Trust (202802/Z/16/Z), the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009). Mass spectrometry and analysis were performed by E.S. Ho, J.P. Xu, and C. Mesaros supported by the National Institute of Environmental Health Sciences grant P30ES013508. We are grateful to J. Tobias and the Penn Molecular Profiling Facility for help with processing the human TCGA data and P. Lal for providing the tissue microarrays. We thank members of the Simon laboratory for helpful comments on the manuscript. Illustrations were generated using Servier medical art.

Publisher Copyright:
© 2021 American Association for Cancer Research.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Groups and Themes

ICEP

Keywords

SCARB1
HDL
ROS
PI3K/AKT
ccRCC

Access to Document

10.1158/2159-8290.CD-21-0211

Full-text PDF (accepted author manuscript)
This is the accepted author manuscript (AAM). The final published version (version of record) is available online via Oxford University Press at 10.1158/2159-8290.CD-21-0211. Please refer to any applicable terms of use of the publisher.
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8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival
Martin, R. M. (Principal Investigator)
1/10/20 → 30/09/25
Project: Research

Cite this

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title = "Cholesterol auxotrophy as a targetable vulnerability in clear cell renal cell carcinoma",

abstract = "Clear cell renal cell carcinoma (ccRCC) is characterized by large intracellular lipid droplets (LDs) containing free and esterified cholesterol; however, the functional significance of cholesterol accumulation in ccRCC cells is unknown. We demonstrate that, surprisingly, genes encoding cholesterol biosynthetic enzymes are repressed in ccRCC, suggesting a dependency on exogenous cholesterol. Mendelian randomization analyses performed on 31,000 individuals indicate a causal link between elevated circulating high-density lipoprotein (HDL) cholesterol and ccRCC risk. Depriving ccRCC cells of either cholesterol or HDL compromises proliferation and survival in vitro and tumor growth in vivo; in contrast, elevated dietary cholesterol promotes tumor growth. Scavenger Receptor B1 (SCARB1) is uniquely required for cholesterol import, and inhibiting SCARB1 is sufficient to cause ccRCC cell cycle arrest, apoptosis, elevated intracellular reactive oxygen species levels and decreased PI3K/AKT signaling. Collectively, we reveal a cholesterol dependency in ccRCC and implicate SCARB1 as a novel therapeutic target for treating kidney cancer.",

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author = "Romain Riscal and Bull, \{Caroline J\} and Mattias Johansson and Timpson, \{Nicholas John\} and Vincent, \{Emma E\} and Simon, \{M Celeste\}",

note = "Funding Information: We acknowledge the NIH grants P01CA104838 and R35CA197602 (to M.C. Simon, which support N. Skuli), and Damon Runyon postdoctoral fellowship DRG2326-18 (to R. Riscal). Mendelian randomization and analysis were performed by E.E. Vincent and C.J. Bull supported by Diabetes UK (17/0005587), the Wellcome Trust (202802/Z/16/Z), the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG\_2019\_2009). Mass spectrometry and analysis were performed by E.S. Ho, J.P. Xu, and C. Mesaros supported by the National Institute of Environmental Health Sciences grant P30ES013508. We are grateful to J. Tobias and the Penn Molecular Profiling Facility for help with processing the human TCGA data and P. Lal for providing the tissue microarrays. We thank members of the Simon laboratory for helpful comments on the manuscript. Illustrations were generated using Servier medical art. Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",

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AU - Bull, Caroline J

AU - Johansson, Mattias

AU - Timpson, Nicholas John

AU - Vincent, Emma E

AU - Simon, M Celeste

N1 - Funding Information: We acknowledge the NIH grants P01CA104838 and R35CA197602 (to M.C. Simon, which support N. Skuli), and Damon Runyon postdoctoral fellowship DRG2326-18 (to R. Riscal). Mendelian randomization and analysis were performed by E.E. Vincent and C.J. Bull supported by Diabetes UK (17/0005587), the Wellcome Trust (202802/Z/16/Z), the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009). Mass spectrometry and analysis were performed by E.S. Ho, J.P. Xu, and C. Mesaros supported by the National Institute of Environmental Health Sciences grant P30ES013508. We are grateful to J. Tobias and the Penn Molecular Profiling Facility for help with processing the human TCGA data and P. Lal for providing the tissue microarrays. We thank members of the Simon laboratory for helpful comments on the manuscript. Illustrations were generated using Servier medical art. Publisher Copyright: © 2021 American Association for Cancer Research.

PY - 2021/12

Y1 - 2021/12

N2 - Clear cell renal cell carcinoma (ccRCC) is characterized by large intracellular lipid droplets (LDs) containing free and esterified cholesterol; however, the functional significance of cholesterol accumulation in ccRCC cells is unknown. We demonstrate that, surprisingly, genes encoding cholesterol biosynthetic enzymes are repressed in ccRCC, suggesting a dependency on exogenous cholesterol. Mendelian randomization analyses performed on 31,000 individuals indicate a causal link between elevated circulating high-density lipoprotein (HDL) cholesterol and ccRCC risk. Depriving ccRCC cells of either cholesterol or HDL compromises proliferation and survival in vitro and tumor growth in vivo; in contrast, elevated dietary cholesterol promotes tumor growth. Scavenger Receptor B1 (SCARB1) is uniquely required for cholesterol import, and inhibiting SCARB1 is sufficient to cause ccRCC cell cycle arrest, apoptosis, elevated intracellular reactive oxygen species levels and decreased PI3K/AKT signaling. Collectively, we reveal a cholesterol dependency in ccRCC and implicate SCARB1 as a novel therapeutic target for treating kidney cancer.

AB - Clear cell renal cell carcinoma (ccRCC) is characterized by large intracellular lipid droplets (LDs) containing free and esterified cholesterol; however, the functional significance of cholesterol accumulation in ccRCC cells is unknown. We demonstrate that, surprisingly, genes encoding cholesterol biosynthetic enzymes are repressed in ccRCC, suggesting a dependency on exogenous cholesterol. Mendelian randomization analyses performed on 31,000 individuals indicate a causal link between elevated circulating high-density lipoprotein (HDL) cholesterol and ccRCC risk. Depriving ccRCC cells of either cholesterol or HDL compromises proliferation and survival in vitro and tumor growth in vivo; in contrast, elevated dietary cholesterol promotes tumor growth. Scavenger Receptor B1 (SCARB1) is uniquely required for cholesterol import, and inhibiting SCARB1 is sufficient to cause ccRCC cell cycle arrest, apoptosis, elevated intracellular reactive oxygen species levels and decreased PI3K/AKT signaling. Collectively, we reveal a cholesterol dependency in ccRCC and implicate SCARB1 as a novel therapeutic target for treating kidney cancer.

KW - SCARB1

KW - HDL

KW - ROS

KW - PI3K/AKT

KW - ccRCC

U2 - 10.1158/2159-8290.CD-21-0211

DO - 10.1158/2159-8290.CD-21-0211

M3 - Article (Academic Journal)

C2 - 34244212

SN - 2159-8274

VL - 11

SP - 3106

EP - 3125

JO - Cancer Discovery

JF - Cancer Discovery

IS - 12

ER -

Cholesterol auxotrophy as a targetable vulnerability in clear cell renal cell carcinoma

Abstract

Bibliographical note

UN SDGs

Research Groups and Themes

Keywords

Access to Document

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Projects

8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival

Cite this