The Origins of Phenotypic Heterogeneity in Cancer

Heterogeneity is a pervasive feature of cancer, and understanding the sources and regulatory mechanisms underlying heterogeneity could provide key insights to help improve the diagnosis and treatment of cancer. In this review, we discuss the origin of heterogeneity in the phenotype of individual cancer cells. Genotype-phenotype (G-P) maps are widely used in evolutionary biology to represent the complex interactions of genes and the environment that lead to phenotypes that impact fitness. Here, we present the rationale of an extended G-P (eG-P) map with a cone structure in cancer. The eG-P cone is formed by cells that are similar at the genome layer but gradually increase variability in the epigenome, transcriptome, proteome, metabolome, and signalome layers to produce large variability at the phenome layer. Experimental evidence from single-cell-omits analyses supporting the cancer eG-P cone concept is presented, and the impact of epimutations and the interaction of cancer and tumor microenvironmental eG-P cones are integrated with the current understanding of cancer biology. The eG-P cone concept uncovers potential therapeutic strategies to reduce cancer evolution and improve cancer treatment. More methods to study phenotypes in single cells will be the key to better understand cancer cell fitness in tumor biology and therapeutics.

Automated summary

Heterogeneity is a common characteristic of cancer, and understanding its underlying mechanisms can provide valuable insights for cancer diagnosis and treatment. This review discusses the origin of heterogeneity in individual cancer cells and presents the concept of an extended G-P cone structure, which explains the gradual increase in variability across multiple molecular layers leading to phenotypic diversity. Experimental evidence and the interaction of cancer cells with the tumor microenvironment are also discussed in relation to the eG-P cone concept. The concept can potentially guide therapeutic strategies to reduce cancer evolution and improve treatment outcomes.