Intratumoral Heterogeneity: More Than Just Mutations

Abstract

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.

Keywords: epigenetic; histone demethylase; transcriptomic heterogeneity.

Figure 1.. Intratumoral cellular genetic heterogeneity and drug-tolerant persisters.

Human tumors often display intratumoral heterogeneity for various biological features. Intratumoral heterogeneity can be due to the presence of multiple genetically distinct subclones within a single tumor (left). Drug-tolerant persisters (DTPs) constitute a subpopulation of genetically homogenous tumor cells (right). Epigenetically distinct tumor cell subpopulations allow for reversible transitions from drug-sensitive to drug-tolerant states.

Figure 2.. Evolutionary trajectories and transcriptomic heterogeneity.

Tumors develop along several evolutionary trajectories. Driver mutations have a selective advantage during cancer progression, and each genetically distinct subclone can exhibit substantial phenotypic variation due to cellular transcriptomic heterogeneity. Transcriptomic heterogeneity can be a consequence of stochastic noise in gene expression.

Figure 3.. Epigenetic regulation of transcriptomic heterogeneity.

Epigenetic modulators such as histone H3K4 demethylases can impact cellular transcriptomic heterogeneity directly. Broad H3K4me3 promoter peaks can lead to rapid events of active transcription leading to smaller fluctuations in gene expression (right), whereas narrow H3K4me3 peak could result in rare events of active transcription (left). Larger fluctuations in gene expression lead to more heterogeneous gene expression patterns within cancer cell populations, thus increasing the possibility that a subpopulation of cancer cells is resistant to anti-cancer therapies. Epigenetic agents may improve the efficacy of cancer therapies by modulating cellular transcriptomic heterogeneity.