The Dynamic m6A Epitranscriptome in Glioma Stem Cell Plasticity and Function

Abstract

Glioblastoma multiforme is one of the most aggressive tumors of the central nervous system. The current standard-of-care includes maximal resection followed by chemotherapy, radiation and more recently, tumor treating fields (TTFs). Despite this multimodal approach, glioblastoma remains refractory to therapy. Glioblastoma resistance, recurrence and malignancy are believed to be driven by a subpopulation of glioma stem cells (GSCs) within the tumor bulk which are characterized by the retention of self-renewal potential as well as the capacity to recapitulate tumor heterogeneity. Within the dynamic intratumoral niche, GSCs demonstrate a high degree of cellular plasticity, reversibly interconverting between stem-like states and more differentiated states as a result of environmental cues/signaling fluctuations. Such plastic adaptive properties are mostly driven by multiple dynamic, reversible epigenetic modifications. We posit that reversible post-transcriptional methylation of RNA transcripts at the m6A position may be one such regulatory mechanism employed by GSCs to efficiently maintain plasticity and adaptive phenotypic transitions. In this section, we discuss the concept of cellular plasticity, introduce dynamic m6a epitranscriptomic mechanisms as potential key regulators of GSC plasticity and finally propose epigenetic based therapeutics as a mean of attenuating glioblastoma plasticity to improve patient outcome.