Tumor evolution and compositional heterogeneity. A, Evolution drives heritable heterogeneity and subsequent outgrowth of malignant clones. Selection pressures from the local microenvironment (e.g. hypoxia, secretion of growth-inhibiting factors, chemotherapeutic agents, etc.) challenge tumor cell survival, often resulting in cell death in early cancer initiation. In order to survive these in a given tissue niche, cancer cells must acquire mutations that promote survival and tumor formation with regard to spatiotemporal context. Robust cells capable of surviving multiple selection events acquire proliferative advantages, eventually resulting in tumor progression and evidence of genetic heterogeneity within a tumor. B, Snapshots of natural selection events within the TME paint a heterogeneous portrait of tumor composition in a spatial context. The TME refers to both the tumor and its local environment of diverse resident and migratory cell types. 1) Infiltrated immune cells shape the tumor development; 2) Tumor stromal cells interact with tumor cells and change the local cancer stem cell niche; 3) Bi-directional plasticity between stem-like cancer cells and tumor cells. 4) Disseminated tumor cells.