Glioblastoma Stem Cells: Driving Resilience through Chaos

Abstract

Glioblastoma is an aggressive and heterogeneous tumor in which glioblastoma stem cells (GSCs) are at the apex of an entropic hierarchy and impart devastating therapy resistance. The high entropy of GSCs is driven by a permissive epigenetic landscape and a mutational landscape that revokes crucial cellular checkpoints. The GSC population encompasses a complex array of diverse microstates that are defined and maintained by a wide variety of attractors including the complex tumor ecosystem and therapeutic intervention. Constant dynamic transcriptional fluctuations result in a highly adaptable and heterogeneous entity primed for therapy evasion and survival. Analyzing the transcriptional, epigenetic, and metabolic landscapes of GSC dynamics in the context of a stochastically fluctuating tumor network will provide novel strategies to target resistant populations of GSCs in glioblastoma.

Keywords: cancer stem cell; entropy; glioblastoma; heterogeneity; therapy resistance; tumor evolution.

Figure 1.. Attractor state model of glioblastoma.

GSCs at the center of the tumor hierarchy have the highest entropy and capacity for adaptation. Attractor states (e.g. microenvironmental niches, genetic mutations, therapeutic intervention) drive the development of different tumor cell populations. Each colored petal depicts different attractor states which drives the proportion of each cellular state. Arrow on the different cellular state represent the directionality allowed on presence of attractor state. Abbreviations: GSC, glioblastoma stem cell

Figure 2.. Glioblastoma stem cells across tumor niches.

GSCs are found in each tumor microenvironments and maintain heterogeneity through unique cell-cell interactions and niche properties throughout the tumor. These niches are not stable and independent, but instead are dynamic drivers of cellular adaptation and resistance, communicating and interconverting as the tumor grows and adapts. Abbreviations: GSC, glioblastoma stem cell

Figure 3.. Therapeutic approach to glioblastoma stem cell adaptation and heterogeneity.

i) Classical therapeutic approaches often spare the GSC population or target individual components of the tumor landscape – e.g. tumor vasculature or rapidly dividing cell populations. This generates new attractor states along with the older untreated states and allows for the tumor to evolve and repopulate. ii) The attractor state model implies that effective therapy will require a combinatorial approach. The first treatment bottlenecks tumor adaptation by applying an initial stimulus that drives cells towards one state, and the second intervention is targeted at the resulting specific cellular state. Abbreviations: GSC, glioblastoma stem cell