CSIG-18. LCLAT1 REGULATES CARDIOLIPIN COMPOSITION, MITOCHONDRIAL PHENOTYPE, AND ONCOGENIC SIGNALING NETWORKS IN ETMR

Abstract BACKGROUND Embryonal tumor with multilayered rosettes (ETMR) is an aggressive pediatric brain tumor that carries a poor prognosis and there is currently no standard of care. Dysregulated mitochondrial bioenergetics and dynamics have been associated with the progression of diverse cancers. Cardiolipins are mitochondrial-specific lipids, and their fatty acid composition has been shown to regulate mitochondrial structure and function. Despite the known functional significance of cardiolipins, their structure-specific accumulation in relation to mitochondrial phenotypes and cellular function in ETMR remains ill-defined. METHODS Spatial lipidomic profiles in patient samples and 3D models were determined using mass spectrometry imaging. Cell proliferation and mitochondrial bioenergetics and dynamics were characterized using immunohistochemistry, transmission electron microscopy, western blotting and metabolic assays. LCLAT1 KD was carried out using siRNA. RESULTS We detected a structure-specific accumulation of cardiolipins and increased expression of the cardiolipin acyl chain remodeling enzyme, lysocardiolipin acyltransferase 1 (LCLAT1) within proliferating tumor cells in patient samples and the 3D tumorspheres. Orthogonal imaging techniques correlated the structure-specific accumulation of cardiolipins with fragmented mitochondria displaying aberrant cristae structure, altered mitochondrial dynamics, decreased expression of respiratory chain enzymes, and a more glycolytic phenotype. LCLAT1 KD altered cardiolipin profiles, significantly reduced growth and proliferation, decreased Sox2 and N-Myc expression, decreased CDKs and MAPK pathway proteins, increased p53 and p21 expression, and significantly increased LIN28A expression and several glycolytic enzymes. Additional therapeutic targeting of the fragmented mitochondrial phenotype identified also resulted in selective inhibition of ETMR growth and viability. CONCLUSIONS Our findings provide novel insight into ETMR biology based on mitochondrial phenotypes and the fatty acid composition of the multifunctional mitochondrial-specific lipid, cardiolipin. We show, for the first time, ETMR growth reduction, and regulation of tumor suppressors and oncoproteins following fatty acid remodeling of CL. On-going studies: Determine the functional significance of the LIN28A increase in relation to the overall anti-oncogenic profile following LCLAT1-driven cardiolipin remodeling, with a focus on differentiation pathways.