TMET-58. Exploring the role of chemerin in modulating lipid metabolism and immune interactions in glioblastoma

Abstract Glioblastoma multiforme (GBM) is among the most most common and lethal primary brain tumors in adults, with a median survival of just 15 months despite current clinical treatments. This underscores the urgent need for novel therapeutic strategies. Metabolic rewiring is a hallmark of cancer and lipid homeostasis has gained an increasingly appreciated role in cancer cell survival. The disruption of lipid metabolic balance can lead to lipotoxicity, creating a new avenue in GBM treatment. Therefore, identifying methods to disrupt said lipid metabolic balance in GBM could provide a needed foothold. Previous studies from the lab have identified chemerin, a multifunctional adipokine encoded by the retinoic acid receptor responder 2 (RARRES2) gene, as an important and targetable lipid metabolism modulator in Clear cell renal cell carcinoma (ccRCC). Chemerin has also been implicated in the mesenchymal-phenotype promoting network between GBM cells and tumor-associated macrophages. We hypothesize that chemerin drives GBM development through lipid metabolism regulation in addition to immune cell trafficking. This study aims to investigate the role and therapeutic opportunities of altered lipid metabolism in GBM and its connections to the TIME by examining chemerin and its receptors (CMKLR1 and GPR1). Immunocompetent GBM mouse models generated through CRISPR-in utero electroporation (IUE) show that mice bearing RARRES2 and CMKLR1 knockout tumors have prolonged survival. In addition, in vitro molecular inhibition of CMKLR1 in both human and murine GBM cell lines result in cell death. In vitro CRISPR knockouts of RARRES2, CMKLR1, and GPR1 aim to elucidate the mechanism by which in vivo inhibition of chemerin signaling results in slower tumor progression. The creation of RARRES2, CMKLR1, and GPR1 whole-body knockout mice via the improved-Genome editing via Oviductal Nucleic Acids Delivery (i-GONAD) method aim to identify the role of tumor specific chemerin expression compared to systemic and immune system specific expression.