VHL mutation drives human clear cell renal cell carcinoma progression through PI3K/AKT-dependent cholesteryl ester accumulationResearch in context
Shuo Zhang,
Tinghe Fang,
Yexuan He,
Weichen Feng,
Zhuoyang Yu,
Yaoyao Zheng,
Chi Zhang,
Shuai Hu,
Zhuojun Liu,
Jia Liu,
Jian Yu,
Han Zhang,
Anbang He,
Yanqing Gong,
Zhisong He,
Kaiwei Yang,
Zhijun Xi,
Wei Yu,
Liqun Zhou,
Lin Yao,
Shuhua Yue
Affiliations
Shuo Zhang
Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Institute of Medical Photonics, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100191, China
Tinghe Fang
Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Institute of Medical Photonics, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100191, China
Yexuan He
Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Institute of Medical Photonics, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100191, China
Weichen Feng
Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Institute of Medical Photonics, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100191, China
Zhuoyang Yu
Department of Urology, Peking University First Hospital, Beijing, 100034, China
Yaoyao Zheng
Department of Urology, Peking University First Hospital, Beijing, 100034, China
Chi Zhang
Department of Urology, Peking University First Hospital, Beijing, 100034, China
Shuai Hu
Department of Urology, Peking University First Hospital, Beijing, 100034, China
Zhuojun Liu
School of Engineering Medicine, Beihang University, Beijing, 100191, China
Jia Liu
School of Engineering Medicine, Beihang University, Beijing, 100191, China
Jian Yu
School of Engineering Medicine, Beihang University, Beijing, 100191, China
Han Zhang
Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Institute of Medical Photonics, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100191, China
Anbang He
Department of Urology, Peking University First Hospital, Beijing, 100034, China
Yanqing Gong
Department of Urology, Peking University First Hospital, Beijing, 100034, China
Zhisong He
Department of Urology, Peking University First Hospital, Beijing, 100034, China
Kaiwei Yang
Department of Urology, Peking University First Hospital, Beijing, 100034, China
Zhijun Xi
Department of Urology, Peking University First Hospital, Beijing, 100034, China
Wei Yu
Department of Urology, Peking University First Hospital, Beijing, 100034, China
Liqun Zhou
Department of Urology, Peking University First Hospital, Beijing, 100034, China
Lin Yao
Department of Urology, Peking University First Hospital, Beijing, 100034, China; Corresponding author.
Shuhua Yue
Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Institute of Medical Photonics, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100191, China; Corresponding author.
Summary: Background: Cholesteryl ester (CE) accumulation in intracellular lipid droplets (LDs) is an essential signature of clear cell renal cell carcinoma (ccRCC), but its molecular mechanism and pathological significance remain elusive. Methods: Enabled by the label-free Raman spectromicroscopy, which integrated stimulated Raman scattering microscopy with confocal Raman spectroscopy on the same platform, we quantitatively analyzed LD distribution and composition at the single cell level in intact ccRCC cell and tissue specimens in situ without any processing or exogenous labeling. Since we found that commonly used ccRCC cell lines actually did not show the CE-rich signature, primary cancer cells were isolated from human tissues to retain the lipid signature of ccRCC with CE level as high as the original tissue, which offers a preferable cell model for the study of cholesterol metabolism in ccRCC. Moreover, we established a patient-derived xenograft (PDX) mouse model that retained the CE-rich phenotype of human ccRCC. Findings: Surprisingly, our results revealed that CE accumulation was induced by tumor suppressor VHL mutation, the most common mutation of ccRCC. Moreover, VHL mutation was found to promote CE accumulation by upregulating HIFα and subsequent PI3K/AKT/mTOR/SREBPs pathway. Inspiringly, inhibition of cholesterol esterification remarkably suppressed ccRCC aggressiveness in vitro and in vivo with negligible toxicity, through the reduced membrane cholesterol-mediated downregulations of integrin and MAPK signaling pathways. Interpretation: Collectively, our study improves current understanding of the role of CE accumulation in ccRCC and opens up new opportunities for treatment. Funding: This work was supported by National Natural Science Foundation of China (No. U23B2046 and No. 62027824), National Key R&D Program of China (No. 2023YFC2415500), Fundamental Research Funds for the Central Universities (No. YWF-22-L-547), PKU-Baidu Fund (No. 2020BD033), Peking University First Hospital Scientific and Technological Achievement Transformation Incubation Guidance Fund (No. 2022CX02), and Beijing Municipal Health Commission (No. 2020-2Z-40713).
