Intratumoral Heterogeneity: More Than Just Mutations

Most human tumors are composed of genetically and phenotypically heterogeneous cancer cell populations, which poses a major challenge for the clinical management of cancer patients. Advances of single-cell technologies have allowed the profiling of tumors at unprecedented depth, which, in combination with newly developed computational tools, enable the dissection of tumor evolution with increasing precision. However, our understanding of mechanisms that regulate intratumoral heterogeneity and our ability to modulate it has been lagging behind. Recent data demonstrate that epigenetic regulators, including histone demethylases, may control the cell-to-cell variability of transcriptomes and chromatin profiles and they may modulate therapeutic responses via this function. Thus, the therapeutic targeting of epigenetic enzymes may be used to decrease intratumoral cellular heterogeneity and treatment resistance, when used in combination with other types of agents. Tumorigenesis is a process of Darwinian evolution driven by cellular heterogeneity for phenotypic features combined with selection.Cancer cells display startling genetic and transcriptomic heterogeneity that increases the probability of therapeutic resistance.Microenvironmental factors such as hypoxia and inflammation have major impact on cellular heterogeneity within tumors.Drug-tolerant persister cells are characterized by specific epigenetic states that are reversible.Cellular transcriptomic heterogeneity could be due to noise in transcription and is modulated by epigenetic regulators such as the KDM5 family of histone H3 lysine 4 demethylases.Combination of epigenetic agents that decrease cellular transcriptomic heterogeneity with targeted or chemotherapies enhances treatment efficacy and reduces the emergence of resistant subpopulations.