MODL-25. ANALYSIS OF TUMOR CELL HETEROGENEITY IN A HUMAN NEURAL PROGENITOR-BASED MODEL OF GLIOBLASTOMA REVEALS NEURODEVELOPMENTAL PROGRAMS AND CYTOSKELETAL DYNAMICS

Abstract Glioblastoma (GBM) is the most common primary malignant neoplasm with poor survival despite treatment. Developing effective therapies remains challenging due to intratumoral heterogeneity, which drives therapeutic resistance and recurrence. To understand how genetic events alter epigenome enhance clonal fitness, we developed an isogenic human neural progenitor cell (NPC)-based model of proneural (PRO) GBM subtype. We introduced TERT promoter (TERTp) C228T gain-of-function TP53 R248Q mutations in H1 embryonic stem cells. Wildtype (WT) cells, single TERTp, double TERTp/TP53 mutants underwent differentiation NPCs. Lentiviral transduction PDGFRA D842V resulted triple mutant PRO Bulk transcriptomics our system revealed hundreds gene expression changes increased mesoderm mesenchymal (MES) subtype signatures TERTp mutants, versus WT mutation telomerase activity, conferring proliferative advantage immortalization NPCs astrocytes. Additionally, was further mutants. Surprisingly, NPCs, WT, displayed < 100 differentially expressed genes, associated neurodevelopmental dynamic cytoskeletal processes. Evolution analyses using counts signature splicing dynamics a developmental trajectory from additive Only formed tumors after intracranial injection athymic nude mice, mean days. Tumors presented histopathological features GBM, transcriptomic evolution immune-interacting both progenitor- neuronal-like subpopulations, similar cycling signatures. Transcription factor genes related WNT signaling lineage commitment as well glial neuronal exhibited epigenetic selection vivo, also observed vitro. Our thus provides opportunity for dissection functional mechanisms underlying serial during tumor evolution.