Serum-free culture success of glial tumors is related to specific molecular profiles and expression of extracellular matrix–associated gene modules

Abstract

Recent molecular characterization studies have identified clinically relevant molecular subtypes to coexist within the same histological entities of glioma. Comparative studies between serum-supplemented and serum-free (SF) culture conditions have demonstrated that SF conditions select for glioma stem-like cells, which superiorly conserve genomic alterations. However, neither the representation of molecular subtypes within SF culture assays nor the molecular distinctions between successful and nonsuccessful attempts have been elucidated. A cohort of 261 glioma samples from varying histological grades was documented for SF culture success and clinical outcome. Gene expression and single nucleotide polymorphism arrays were interrogated on a panel of tumors for comparative analysis of SF+ (successful cultures) and SF- (unsuccessful cultures). SF culture outcome was correlated with tumor grade, while no relation was found between SF+ and patient overall survival. Copy number-based hierarchical clustering revealed an absolute separation between SF+ and SF- parental tumors. All SF+ cultures are derived from tumors that are isocitrate dehydrogenase 1 (IDH1) wild type, chromosome 7 amplified, and chromosome 10q deleted. SF- cultures derived from IDH1 mutant tumors demonstrated a fade-out of mutated cells during the first passages. SF+ tumors were enriched for The Cancer Genome Atlas Classical subtype and intrinsic glioma subtype-18. Comparative gene ontology analysis between SF+ and SF- tumors demonstrated enrichment for modules associated with extracellular matrix composition, Hox-gene signaling, and inflammation. SF cultures are derived from a subset of parental tumors with a shared molecular background including enrichment for extracellular matrix-associated gene modules. These results provide leads to develop enhanced culture protocols for glioma samples not propagatable under current SF conditions.