P01.13 The role of non-coding RNAs in GBM stem-like cells subtype identity maintenance and transition

Abstract

AbstractDecades of research on protein coding genes (2% of the genome) led to only incremental improvements of outcomes in glioblastoma multiforme (GBM) patients. Meanwhile, research on non-protein-coding genes, which constitute the vast majority of the human transcriptome, have received comparatively little attention to date. Large scale transcriptomic profiling of GBM into four subtypes has provided remarkable insight about the pathobiology and heterogeneous nature of this disease, including the mechanisms of subtype maintenance and adaptation to tumor anatomic niche and microenvironmental challenges. The co-existence of several molecular subtypes of differentiated tumor cells and GBM stem-like cells (GSCs) within individual tumors is further complicated by their complex speciation, inter-subtype transitions and hybrid stages. The role of non-coding RNAs (such as microRNAs and long, non-coding RNAs) in these processes is poorly understood. Through their unique capability of targeting multiple mRNA targets, microRNAs, whose expression is often de-regulated in cancers, play pivotal role in pathophysiology of tumor. Subtype-specific expression of microRNA-128 (miR-128) affects complex subpopulation dynamics within the heterogeneous GBM tumors. Alterations in miR-128 levels, acting through de-regulation of multiple mRNA targets that control epigenetic landscape, are a potent mechanism of bi-directional transitions between proneural and mesenchymal GSC subpopulations resulting in intermediate hybrid stages and emphasizing highly intricate intra-tumoral networking. Long non-coding RNAs (lncRNAs) have an undefined role in the pathobiology of GBM. Hypoxia Inducible Factor 1 Alpha-Anti Sense RNA 2 (HIF1A-AS2) was identified as a subtype-specific hypoxia-inducible lncRNA, upregulated in mesenchymal GSCs. Knockdown of HIF1A-AS2 affected GSC growth, self-renewal, and hypoxia-dependent molecular reprogramming, leading to delayed growth of mesenchymal GSC tumors, survival benefits, and impaired expression of downstream genes. Our data demonstrate that HIF1A-AS2 contributes to GSCs’ speciation and adaptation to hypoxia within the tumor microenvironment, acting directly through its interactome and targets and indirectly by modulating responses to hypoxic stress depending on the subtype-specific genetic context. These examples highlight immense, yet not fully appreciated, role of non-coding RNAs in pathophysiology of GBM.