Drivers of dynamic intratumor heterogeneity and phenotypic plasticity

Abstract

Cancer is a clonal disease, i.e., all tumor cells within a malignant lesion trace their lineage back to a precursor somatic cell that acquired oncogenic mutations during development and aging. And yet, those tumor cells tend to have genetic and nongenetic variations among themselves-which is denoted as intratumor heterogeneity. Although some of these variations are inconsequential, others tend to contribute to cell state transition and phenotypic heterogeneity, providing a substrate for somatic evolution. Tumor cell phenotypes can dynamically change under the influence of genetic mutations, epigenetic modifications, and microenvironmental contexts. Although epigenetic and microenvironmental changes are adaptive, genetic mutations are usually considered permanent. Emerging reports suggest that certain classes of genetic alterations show extensive reversibility in tumors in clinically relevant timescales, contributing as major drivers of dynamic intratumor heterogeneity and phenotypic plasticity. Dynamic heterogeneity and phenotypic plasticity can confer resistance to treatment, promote metastasis, and enhance evolvability in cancer. Here, we first highlight recent efforts to characterize intratumor heterogeneity at genetic, epigenetic, and microenvironmental levels. We then discuss phenotypic plasticity and cell state transition by tumor cells, under the influence of genetic and nongenetic determinants and their clinical significance in classification of tumors and therapeutic decision-making.

Keywords: cancer evolution; cell state transition; drug resistance; intratumor heterogeneity; phenotypic plasticity.

Figure 1.

Intrapatient tumor heterogeneity at multiple levels. Tumors represent complex dynamic systems comprising different subclones, heterogeneous in both genotype and phenotype, and regulated by cell-intrinsic and -extrinsic factors. The clonal evolution model (top right) depicts the accumulation of mutations and clonal evolutionary dynamics that follows. Genetic heterogeneity arises due to somatic mutations occurring in different tumor cell lineages within the same malignant growth. Epigenetic heterogeneity (middle right) develops due to changes in epigenetic states in different tumor cells, sometimes within the same tumor subclones, and such changes can be potentially reversible. Genetic and nongenetic variations collectively result in phenotypic diversity of the tumor cells. Phenotypically diverse tumor cells interact with immune and stromal cells in varied microenvironmental contexts (bottom right) to promote tumor heterogeneity. *Genetic alterations, while the shades of blue represent epigenetic and/or phenotypic heterogeneity in tumor cells. Stromal and immune cells are shown in yellow, orange, and red, respectively.

Figure 2.

Genetic drivers of dynamic heterogeneity in tumors. A: reversal mutations during tumor progression restore cancer gene function or compensate for gain- or loss-of-function at the pathway-level. *Genetic alterations on the same gene or on different genes. B: dynamic changes in telomerase expression and telomere length heterogeneity with implications for genomic instability during cancer progression. Different colors (blue and orange) display telomeres of different lengths. C: examples of genetic drivers of dynamic heterogeneity in cancer by copy number variation. Red empty ovals represent extrachromosomal circular DNA (left), and green and yellow filled ovals represent varied proportion of mutated and wild-type mitochondrial DNA (right). Replication and asymmetric distributions can lead to skewed distributions, and dynamic heterogeneity in tumors.