Cancer cell heterogeneity and plasticity: A paradigm shift in glioblastoma

Abstract

Phenotypic plasticity has emerged as a major contributor to intra-tumoral heterogeneity and treatment resistance in cancer. Increasing evidence shows that glioblastoma (GBM) cells display prominent intrinsic plasticity and reversibly adapt to dynamic microenvironmental conditions. Limited genetic evolution at recurrence further suggests that resistance mechanisms also largely operate at the phenotypic level. Here we review recent literature underpinning the role of GBM plasticity in creating gradients of heterogeneous cells including those that carry cancer stem cell (CSC) properties. A historical perspective from the hierarchical to the nonhierarchical concept of CSCs towards the recent appreciation of GBM plasticity is provided. Cellular states interact dynamically with each other and with the surrounding brain to shape a flexible tumor ecosystem, which enables swift adaptation to external pressure including treatment. We present the key components regulating intra-tumoral phenotypic heterogeneity and the equilibrium of phenotypic states, including genetic, epigenetic, and microenvironmental factors. We further discuss plasticity in the context of intrinsic tumor resistance, where a variable balance between preexisting resistant cells and adaptive persisters leads to reversible adaptation upon treatment. Innovative efforts targeting regulators of plasticity and mechanisms of state transitions towards treatment-resistant states are needed to restrict the adaptive capacities of GBM.

Keywords: glioblastoma; plasticity; treatment resistance; tumor heterogeneity; tumor microenvironment.

Fig. 1

Dynamic organization of phenotypic heterogeneity in GBM. The creation of phenotypic heterogeneity in GBM differs from the hierarchical differentiation process of normal stem cells. Neural stem cells create various committed progenitors and differentiated cells in a unidirectional hierarchical process. Reversibility of the differentiation process is very limited and can occur only between closely related progenitors and stem cell populations. In contrast, GBM constitutes dynamic and diverse tumor cell populations, where high plasticity is retained in all cells and differences between CSC-like and differentiated-like states are rather small. GBM cells exist in gradients of transcriptomic states, with multiple axes of variation. Interchanges have been documented between TCGA subtypes (Proneural, Classical, Mesenchymal), single-cell states (Neural progenitor cell (NPC)-like, Oligodendrocyte progenitor cell (OPC)-like, Astrocyte (Astro)-like and Mesenchymal (Mes)-like) as well as CSC-like and differentiated-like states. The phenotypic equilibrium at the population level is dictated by the genetic background, TME cues and treatment. Created with Biorender.com.

Fig. 2

Intrinsic and microenvironmental features of the GBM ecosystem defining plasticity and intra-tumoral heterogeneity. The GBM cellular ecosystem comprises of diverse tumor cells residing in different TME niches. Tumor cell plasticity and the equilibrium of phenotypic states at the population level is defined by multiple tumor-intrinsic features and extrinsic cues from the TME. Created with Biorender.com.

Fig. 3

Tumor heterogeneity and plasticity as resistance mechanisms. Tumors contain cells with varying sensitivity to treatment. Treatment leads to the eradication of drug-sensitive cells. Resistance can be driven by Darwinian selection of preexisting resistant cells with advantageous genetic or phenotypic tumor characteristics. Highly resistant genetic clones may also be acquired upon treatment (ie, clonal evolution and selection). Adaptive resistance is driven by drug-tolerant persisters that survive treatment and adapt towards resistant phenotypic states. Persisters can revert to their initial phenotypic states and recreate phenotypic heterogeneity when released from the treatment (ie, drug holiday). Drug resistance may thus be a result of reversible epigenetic plasticity combined with irreversible clonal expansion. Created with Biorender.com.