Restraint of cancer cell plasticity by spatial homotypic clustering

Tumor heterogeneity fueled by plasticity of cancer cells is a key to therapy failure. Here, we define the role of proximal communications of malignant cells in glioblastoma plasticity. We find that tumor cell state coherence is maximal in cells organized in homotypic clusters with defined relationships with non-malignant cells, whereas randomly dispersed cells downregulate the original state, acquire alternative phenotypes and exhibit changes in the microenvironment. We demonstrate the intrinsic propensity of glioblastoma cells to develop into clustered and dispersed spatial patterns in orthotopic mouse models and experimentally validate the cell state-specific mechanisms of cell-cell adhesion that prevent phenotype deviation with pharmacologic perturbations in patients-derived glioblastoma models. We establish the generality of "homotypic clustered cell identity" in circulating clustered and single breast cancer cells and show that the glioblastoma glycolytic-plurimetabolic dispersed cellular state uniquely confers shorter survival, thus assigning clinical significance to the spatial patterning of cancer cells in human tumors.