TMET-20. Lipid-dependent regulation of lineage specification and tumor growth In H3K27M-mutant gliomas

Abstract H3K27M-mutant gliomas are lethal pediatric brain tumors driven by progenitor-like cells that subvert normal differentiation but retain some developmental plasticity, as evidenced by the presence of partially differentiated, non-tumorigenic H3K27M-positive cells within the tumor mass. This progenitor-to differentiated fate transition is also induced by the common cell culture supplement, serum. However, the identity of the pro-differentiation serum component is a key unanswered question. Through integrated lipidomic, chromatin, and single-cell transcriptomic analyses, we identify n-3 polyunsaturated fatty acids (n3-PUFAs) as the key serum and dietary components necessary and sufficient to induce differentiation of H3K27M glial progenitors. Remarkably, dietary enrichment of n3-PUFAs triggers this developmental shift in H3K27M-mutant glioma orthotopic models, reduces tumor burden, and increases survival. These findings uncover a previously unrecognized role for n3-PUFAs in governing glioma cell fate with promising therapeutic implications. Ongoing studies are focused on elucidating the molecular mechanisms whereby n3-PUFAs drive this differentiation program.