Emerging Role of Glioma Stem Cells in Mechanisms of Therapy Resistance

Abstract

Since their discovery at the beginning of this millennium, glioma stem cells (GSCs) have sparked extensive research and an energetic scientific debate about their contribution to glioblastoma (GBM) initiation, progression, relapse, and resistance. Different molecular subtypes of GBM coexist within the same tumor, and they display differential sensitivity to chemotherapy. GSCs contribute to tumor heterogeneity and recapitulate pathway alterations described for the three GBM subtypes found in patients. GSCs show a high degree of plasticity, allowing for interconversion between different molecular GBM subtypes, with distinct proliferative potential, and different degrees of self-renewal and differentiation. This high degree of plasticity permits adaptation to the environmental changes introduced by chemo- and radiation therapy. Evidence from mouse models indicates that GSCs repopulate brain tumors after therapeutic intervention, and due to GSC plasticity, they reconstitute heterogeneity in recurrent tumors. GSCs are also inherently resilient to standard-of-care therapy, and mechanisms of resistance include enhanced DNA damage repair, MGMT promoter demethylation, autophagy, impaired induction of apoptosis, metabolic adaptation, chemoresistance, and immune evasion. The remarkable oncogenic properties of GSCs have inspired considerable interest in better understanding GSC biology and functions, as they might represent attractive targets to advance the currently limited therapeutic options for GBM patients. This has raised expectations for the development of novel targeted therapeutic approaches, including targeting GSC plasticity, chimeric antigen receptor T (CAR T) cells, and oncolytic viruses. In this review, we focus on the role of GSCs as drivers of GBM and therapy resistance, and we discuss how insights into GSC biology and plasticity might advance GSC-directed curative approaches.

Keywords: glioblastoma; glioma stem cells; heterogeneity; immune checkpoint; plasticity; therapy resistance.

Figure 1

Simplified, two-dimensional model of dynamic adaptations of highly plastic GSC populations. GSCs (shaded in grey) reside at the center of GBM plasticity giving rise to multiple cellular states (indicated by differently colored GBM cells), thereby driving tumor heterogeneity. Cellular states (each represented by a different color) can be driven by intrinsic and extrinsic factors (e.g., therapeutic intervention, hypoxia, injury response, niche composition, genetic alterations etc., as indicated by “Cellular State Driver A–F”). Cells of a certain state can transition to another cellular state (indicated by dual-colored arrows). Plasticity also produces several intermediate hybrid states that share properties of two cellular states (indicated by cells with intermediate colors between two cellular states). Created with BioRender.com (accessed on 22 June 2023).

Figure 2

Model of GSC subclones driving therapy resistance and recurrence of heterogeneous GBM. Primary heterogeneous GBM (left panel) with GBM cells (rose cells) and plastic GSCs (colored cells). Administration of therapy (middle panel) provides an environment that promotes the selection of subclonal GSC populations, which either already are therapy resistant (blue cell; linear model) or acquire therapy-driven resistance (red cell; divergent model). The resulting GSCs are highly plastic and can seed tumor relapse of heterogeneous recurrent GBM (right panel). Created with BioRender.com (accessed on 17 March 2023).

Figure 3

Proposed therapeutic approach to target highly plastic GSCs in GBM. Highly plastic GBM requires multimodal and sequential therapeutic approaches. The first treatment (anti-GBM therapy) eliminates some cellular states while also driving cells (including GSCs) towards one single state. This post-treatment minimal residual disease (MRD) state exhibits greatly reduced heterogeneity and is now vulnerable to strategies specifically targeting the remaining cellular state. Created with BioRender.com (accessed on 22 June 2023).