Graduate and Postdoctoral Research Symposium 2020 has ended
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Sze Kiat Tan

VHL-Dependent Metabolic Plasticity in Clear Cell Renal Cell Carcinoma Mediated by Chemerin-Driven Suppression of Fatty Acid Oxidation
Poster Presenter #42
Ph.D. in Cancer Biology
Advanced clear cell renal cell carcinoma (ccRCC) leads to death within 5 years for almost 90% of affected individuals due to poor responses to the conventional therapies. Alterations in the VHL tumor suppressor stabilizing the HIFs are the most prevalent molecular features of clear cell tumors. ccRCC is histologically defined by its lipid and glycogen-rich cytoplasmic deposits, yet the significance of lipid deposition in ccRCC remains undefined. Expression profiling has demonstrated that ccRCC displays an adipogenic gene expression signature and is proposed to have undergone adipogenic trans-differentiation. The aim of the current study was to identify the role of adipokine chemerin in lipid metabolism and its regulation of tumor growth in ccRCC. Methodology: The presence of lipid-droplets in cells were analyzed using immunofluorescence. Untargeted lipidomics, metabolomics and RNA-sequencing were performed to analyze the lipid pathways in ccRCC. Subrenal ccRCC xenografts were also used to investigate the therapeutic effect of monoclonal antibodies on tumor growth. Results: Single-cell RNA-sequencing revealed that chemerin expression was significantly elevated in ccRCC tumor versus normal kidney; and clinicopathogical analyses showed that chemerin expression correlates with tumor grade, patient BMI and poor survival. Functionally, suppression of chemerin significantly reduced cell proliferation, DNA synthesis, and lipid deposition of ccRCC cells in vitro and in vivo. We unraveled that chemerin regulates transcription of HIF2a and promotes lipid synthesis in ccRCC by regulating the rate-limiting component of mitochondrial fatty acid transport, CPT1A which is a direct HIF target gene. Chemerin silencing enhanced fatty acid beta-oxidation of fatty acid tails of glycerophospholipids and increased mitochondrial uncoupling, resulting in enhanced lipoapoptosis. Consistent with this finding, [5-13C5]glutamine tracing corroborated that ccRCC reduced reductive carboxylation for de novo lipogenesis after chemerin inhibition. We further discovered that chemerin is regulated by VHL, highlighting a novel regulator clear cell phenotype. In addition, chemerin was elevated in serum of ccRCC patients, suggesting the potential role as a novel serum biomarker. Conclusion: Collectively, these results suggest that chemerin is indispensable in ccRCC biology and targeting lipid metabolism via inhibition of a soluble adipokine is a promising pharmacological approach to greatly expand therapeutic strategies for ccRCC patients, and other lipid-dependent malignancies.

Additional author(s): Iqbal Mahmud, Anthony Grisworld, Michelle Puchowicz, Chase K. A. Neumann, Flavia Fontanesi, Rutulkumar Patel, Mark L. Gonzalgo, J. Mark Brown, Timothy Garrett, Scott Welford