Abstract
Glioblastoma multiforme (GBM) is one of the most common and lethal primary brain tumors in adults. Despite clinical efforts, patient prognosis remains poor with a median survival of approximately 14 months. Thus, identification of novel treatment avenues is needed. Metabolic rewiring is a hallmark of cancer and lipid homeostasis has an increasingly appreciated role in cancer cell survival. It has been shown that 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. Given similarities in GBM and ccRCC lipid metabolism and the existing role of chemerin in the tumor immune microenvironment in GBM, we hypothesize that chemerin drives GBM development by regulating lipid metabolism in addition to immune cell trafficking. This study aims to investigate the role and therapeutic opportunities of altered lipid metabolism in GBM 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, CMKLR1, and GPR1 knockout tumors have prolonged survival. In addition, in vitro molecular inhibition of CMKLR1 in both human and murine GBM cell lines results in cell death. Ongoing studies involving in vitro CRISPR knockouts of RARRES2, CMKLR1, and GPR1 aim to elucidate the mechanisms by which in vivo inhibition of chemerin signaling results in slower tumor progression.