ATRT-18. ELUCIDATING THE ETMR MICROENVIRONMENT USING SPATIAL MULTI-OMICS TECHNOLOGIES

Abstract

Abstract Embryonal tumor with multilayered rosettes (ETMR) is a highly aggressive CNS neoplasm that occurs almost exclusively in infants under 4 years of age and is associated with an extremely poor prognosis. A bottleneck in the development of new and curative treatments for ETMR stems from our limited understanding of the spatiotemporal biological heterogeneity within patient tumor samples and a lack of preclinical models that adequately reflect the entire biological spectrum. Novel lipid-based therapeutics that encompass ganglioside-directed immunotherapy, targeting lipid metabolism and membrane lipid therapy, have shown efficacy in the treatment of brain tumors but have yet to be evaluated in the treatment of ETMR. We carried out mass spectrometry imaging on ETMR patient samples to identify the histology-specific accumulation of lipids within the diverse cell populations of the tumor microenvironment. Our preliminary studies identified the accumulation of glycosphingolipids, cardiolipins, phosphatidylinositols, and ceramide-1-phosphates within tumor cells, including the characteristic multilayered rosettes, and within different microvascular proliferations. All data were correlated to histopathology and Ki67 proliferation index. We next evaluated the lipid profiles in the patient-derived ETMR cell line, BT183, compared to control neural stem cells (NSCs), grown as 3D tumorspheres and neurospheres, respectively. From this data we identified lipids that accumulated in our patient samples and the ETMR cell line but were significantly reduced or not detected in the control NSCs. Analysis aimed at a systems biology approach to study the ETMR microenvironment using imaging mass cytometry for multiplex IHC and spatial transcriptomics to correlate lipidomic phenotype to distinct cell populations within the microenvironment are ongoing. Preclinical model development based on these findings and drug screening of therapeutics targeting these lipidomic pathways are also ongoing.