Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment

Cancer stem cells (CSCs) have been proposed to underlie the hierarchical organization of Glioblastoma (GBM) causing resistance to treatment, however the identity of CSCs in solid tumors remains largely elusive. Here we find that GBM cells expressing cell membrane CSC-associated markers do not represent a clonal entity defined by distinct functional properties and/or transcriptomic profiles, but rather a plastic state that most cancer cells can adopt. We show that phenotypic heterogeneity arises from non-hierarchical, reversible state transitions that are instructed by the microenvironment. While all tested cancer cell subpopulations survive and adjust their phenotype in vivo, their speed of plasticity differs resulting in variable tumor growth rates. Thus CSC-associated phenotypic heterogeneity is a result of stochastic reversible plasticity and increased tumorigenic potential in vivo correlates with fast adapting cell states.