Molecular subtypes and the (in vitro) response of glioblastoma to temozolomide

BACKGROUND: We address the therapeutic relevance of glioblastoma (GBM)'s molecular characterization, focusing on whether a proneural-vs-mesenchymal classification may describe GBM heterogeneity, correlate to stemness and CD44 (a marker often, but conflictingly, used in GBM), and have a prognostic value in terms of temozolomide (TMZ) resistance. METHODS: We molecularly profiled 4 patient-derived GBM cells (PD-GBM) and a reference cell line (U87), validating the results in public datasets (PD-GBM, TCGA-GBM), then studying the subtype-specific response to TMZ in vitro, both under normoxia and simulated hypoxia. RESULTS: ) and inter-tumorally (also in larger datasets). Further, mesenchymal PD-GBM cells are also enriched in other hyaluronic acid (HA) surface receptors, proneural in matrix HA receptors. Finally, although TMZ stimulates a general mesenchymal shift in all cells, there are proneural-specific responses: this subtype resists TMZ better under hypoxia (vs. normoxia) in a first treatment, and in a second treatment (vs. single) under normoxia. CONCLUSION: PD-GBM show clear proneural/stemness and mesenchymal/CD44 correlations, which may bear prognostic significance, as more proneural/stem GBMs appeared more capable to develop TMZ resistance.