Abstract
Simple SummaryGlioblastoma stem-like cells (GSCs) drive the progression and therapeutic resistance of glioblastoma. GSC plasticity allows them to adapt to different microenvironments and to persist after treatments. GSCs can reside in hypoxic, invasive and perivascular niches, which shape their phenotype through the induction of transitions involving metabolic and epigenetic changes. Therefore, the targeting of molecules that dynamically regulate the transcriptional programs of GSCs, and consequently their plasticity, has emerged as a novel therapeutic alternative. In this review, we described the intratumoral heterogeneity of GBM, discussing the role of GSCs niches and epigenetic modifications on the cell plasticity.Glioblastoma (GBM) is the most frequent and aggressive brain tumor, characterized by great resistance to treatments, as well as inter- and intra-tumoral heterogeneity. GBM exhibits infiltration, vascularization and hypoxia-associated necrosis, characteristics that shape a unique microenvironment in which diverse cell types are integrated. A subpopulation of cells denominated GBM stem-like cells (GSCs) exhibits multipotency and self-renewal capacity. GSCs are considered the conductors of tumor progression due to their high tumorigenic capacity, enhanced proliferation, invasion and therapeutic resistance compared to non-GSCs cells. GSCs have been classified into two molecular subtypes: proneural and mesenchymal, the latter showing a more aggressive phenotype. Tumor microenvironment and therapy can induce a proneural-to-mesenchymal transition, as a mechanism of adaptation and resistance to treatments. In addition, GSCs can transition between quiescent and proliferative substates, allowing them to persist in different niches and adapt to different stages of tumor progression. Three niches have been described for GSCs: hypoxic/necrotic, invasive and perivascular, enhancing metabolic changes and cellular interactions shaping GSCs phenotype through metabolic changes and cellular interactions that favor their stemness. The phenotypic flexibility of GSCs to adapt to each niche is modulated by dynamic epigenetic modifications. Methylases, demethylases and histone deacetylase are deregulated in GSCs, allowing them to unlock transcriptional programs that are necessary for cell survival and plasticity. In this review, we described the effects of GSCs plasticity on GBM progression, discussing the role of GSCs niches on modulating their phenotype. Finally, we described epigenetic alterations in GSCs that are important for stemness, cell fate and therapeutic resistance.
Highlights
Glioblastoma (GBM) is the most frequent primary brain tumor accounting for more than 50% of gliomas in all age groups [1]
The use of personalized therapy has been proposed based on the prior identification of the molecular subtype, studies have shown that GBM stem-like cells (GSCs) can shift between one subtype and another
We know that cellular plasticity is a key property for GSCs, as it helps them persist in different niches, ensuring heterogeneity within the tumor (Figure 1)
Summary
Glioblastoma (GBM) is the most frequent primary brain tumor accounting for more than 50% of gliomas in all age groups [1]. GSCs exhibit a flexible transcriptional program that allows them to transit between different cellular substates with distinctive phenotypic and functional characteristics [24,25] Depending on their niche or external factors (such as therapy), GSCs can express a quiescent, proliferative or invasive phenotype or become differentiated cancer cells. Transcriptomic analyses have suggested that GSCs are in a state of high entropy, which translates into a flexible transcriptional program allowing them to make transitions from one phenotypic state to another [56,60,61] This phenomenon would ensure GSCs adaptation to different tumor niches, expanding the options of therapeutic resistance mechanisms. Understanding how attractors shape the cellular phenotype could help us avoid the adaptation, heterogeneity and progression of GBM cells
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