Abstract 2393: Chemerin signaling presents a novel metabolic weakness in clear cell renal cell carcinoma (ccRCC)

Abstract

Abstract Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of kidney cancer,accounting for 70-80% of the cases. While surgical resection of early-stage tumors remains the standard carefor patients, advanced ccRCC, metastatic or recurrent, portends a 5-year survival rate of only 12%, primarilydue to insensitivity toward conventional chemotherapy. ccRCC is identifiable histologically by its dramaticlipid storage phenotype, similar to adipocytes; yet the role of lipid metabolism in ccRCC is poorly understood.One of the well-established risk factors for ccRCC is obesity, and given that adipose tissue is known to producea variety of pro-adipogenic signaling molecules (called adipokines), we hypothesized that adipokine signalingmight be involved in the etiology of ccRCC. Our lab has recently identified a pro-tumorigenic adipokineprotein, chemerin (RARRES2), that is positively correlated with tumor aggressiveness. Suppression of chemerinvia either monoclonal antibody or siRNA led to reduction in lipid storage and significant tumor growthimpairment in both in vitro and in vivo models, suggesting the feasibility of targeting lipid metabolism as atreatment option in ccRCC patients. In this study, we investigate the signaling mechanisms of chemerin andhave found that chemerin drives downstream cellular activities and lipid deposition. We utilized CRISPR toknockout two candidate receptors of chemerin, GPR1 and CMLKR1, to gain insight into the signal transduction.CMLKR1 is a G-protein coupled receptor widely expressed on a variety of immune cells whereas GPR1expression is reported primarily in adipose tissues. While unknown on their detailed signaling cascadez, bothreceptors affect lipid metabolism related gene profiles in our ccRCC cell lines. Furthermore, both GPR1 andCMKLR1 knockout lead to growth suppression and decreased intracellular lipid deposition, highlighting theinvolvement of both receptors in regulating lipid metabolism and conferring growth advantage in ccRCC. Ourdata so far have shown the feasibility of identifying metabolic weaknesses in ccRCC, raising that possibility thattargeting lipid metabolism could be beneficial in ccRCC. Further investigation will be conducted to assess thetargetability of this ligand/receptor axis and various in vivo models including PDX and transgenic will be usedto assess the translational potential of our findings. Citation Format: Dazhi Wang. Chemerin signaling presents a novel metabolic weakness in clear cell renal cell carcinoma (ccRCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2393.