MODL-05. UNDERSTANDING THE METABOLIC VULNERABILITIES IN INFILTRATING GLIOMATOSIS CEREBRI CELLS

Abstract

Abstract BACKGROUND Gliomatosis cerebri (GC), a rare form of high-grade glioma, is characterized by a particularly invasive phenotype within multiple lobes of the brain and a dismal prognosis. This entity was removed in 2016 of the WHO brain tumor classification because of an absence of specific GC driving molecular signature. Its diffusive aspect on MRI is defined by an absence of cohesive tumor mass, a mild contrast enhancement and a rare neoangiogenesis. Based on those observations, our objectives were to understand how these cells are adapting to their brain environment without a physiological nutritive efflux associated to a reduced oxygen concentration and determine a metabolic signature of GC. METHODS Preliminary results in a large cohort of HGGs bearing several drivers (H3.3 G34V, NMYC amplified, BCOR positive) or a more “wildtype” phenotype with new entities (pedRTK 1 and 2) were underlining glucose and glutamine as major nutrients in cell metabolic suppliance. Therefore, epigenetic assessments, bulk metabolomics, and Seahorse technology, as well as labeled glucose and glutamine metabolites study, helped us in pediatric GC-derived cell lines (BT97 and BT139, PEDIAMODECAN program) to understand the role of both nutrients and their central role in GC in hypoxic microenvironment. RESULTS Both glucose and glutamine are involved in carbon fueling biosynthesis in those cells. Glutamine is much more involved in supplying nitrogen to fuel several specific amino acids and mitochondrial metabolisms. Meanwhile, we developed drug testing using Matrigel invasion aspects. The tested drugs were able to reduce invasiveness of GC cells and modify the intratumoral metabolism. CONCLUSION All those observations seem to explain GC cell adaptation into the hypoxic microenvironment, their plasticity and resistance through metabolic reprogramming based on glutaminolysis and glycolysis.