Restraint of cancer cell plasticity by spatial homotypic clustering
Simona Migliozzi, Bruno Adabbo, Luciano Garofano, Fan Wu, Pedro Davila, Ricardo J. Komotar, Michael E. Ivan, Ashish H. Shah, Benjamin Currall, Siôn L. Williams, Daniel Bilbao Cortes, Melinda Boone, Macarena I. de la Fuente, Sakir H. Gultekin, Michele Ceccarelli, Antonio Iavarone, Anna Lasorella
Abstract
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. • Spatial architecture of glioblastoma IDH wild type at single-cell resolution • GBM cells homotypic clustering and dispersion recur across samples and omics • Homotypic clustering locks tumor cell identity while dispersion induces plasticity • Clustering and dispersion are general features of cancer cells impacting prognosis Migliozzi et al. use single-cell resolution spatial transcriptomics of 16 glioblastoma and 2.8 million cells to study tumor architecture. They discover that cell state coherence is maximal in cells organized within homotypic clusters with defined relationships with non-malignant cells. Dispersed cells exhibit greater plasticity, acquiring alternative phenotypes in the microenvironment and being associated with worse prognosis.