Cell- and system-level view of intratumor heterogeneity. (Top) Intrinsic factors (genetic alterations or epigenetic changes) and extrinsic factors (stimuli from the environment) lead to transcriptional changes, represented here with the expression of two genes (orange and purple). (Bottom) Transcriptional heterogeneity is revealed by scRNA-seq, which gives the gene expression profile of each cell. Histograms depict expression profiles corresponding to different cancer cell states in which two genes (orange and purple lines) are expressed at different levels. Within the tumor, cancer cells may also compete or cooperate with each other and interact with other cells of the tumor microenvironment. Intrinsic epigenetic factors may induce the EMT. Low vascularization and oxygen levels (O2) may induce the hypoxic state, which in turn promotes angiogenesis through VEGFA secretion. Interferon gamma (IFNG) secretion by T cells may lead to an interferon response state with high CD274 (also known as PDL1) expression.
