Cancer cells exhibit clonal diversity in phenotypic plasticity

Abstract

Phenotypic heterogeneity in cancers is associated with invasive progression and drug resistance. This heterogeneity arises in part from the ability of cancer cells to switch between phenotypic states, but the dynamics of this cellular plasticity remain poorly understood. Here we apply DNA barcodes to quantify and track phenotypic plasticity across hundreds of clones in a population of cancer cells exhibiting epithelial or mesenchymal differentiation phenotypes. We find that the epithelial-to-mesenchymal cell ratio is highly variable across the different clones in cancer cell populations, but remains stable for many generations within the progeny of any single clone—with a heritability of 0.89. To estimate the effects of combination therapies on phenotypically heterogeneous tumours, we generated quantitative simulations incorporating empirical data from our barcoding experiments. These analyses indicated that combination therapies which alternate between epithelial- and mesenchymal-specific treatments eventually select for clones with increased phenotypic plasticity. However, this selection could be minimized by increasing the frequency of alternation between treatments, identifying designs that may minimize selection for increased phenotypic plasticity. These findings establish new insights into phenotypic plasticity in cancer, and suggest design principles for optimizing the effectiveness of combination therapies for phenotypically heterogeneous tumours.

Toward understanding of the role of reversibility of phenotypic switching in the evolution of resistance to therapy

“…In particular, the former of the two studied models, the quasispecies model, confirmed that under specific symmetric environmental conditions [where according to Eq. (2.1) the replication rates of phenotypic states move in symmetrically opposite directions dr (1) (t) = −dr (0) (t)] the clones with higher reversibility may outcompete their less reversible rivals, which is consistent with recent experimental findings [24]. Accordingly to both presented models, the high degree of reversibility represents an evolutionary advantage in the variable environments which disappears when the environments become static and vice versa.…”

“…In bacteria, the well known riskdiversification strategy evolved in the populations when facing uncertain future and/or environment [13,14,15] is the bet-hedging strategy [16,17,10]. Based on formal similarity of evolving cancer cells population with bacteria, viruses or yeast, it has been recently proposed that the structure of intratumor heterogeneity is evolutionary trait as well, evolving to maximize clonal fitness at a cancerrelevant timescale in changing (or uncertain) environment and that its structure corresponds to the bet-hedging strategy [18,19,20,21,22] which has been recently put into therapeutic context [23,24]. To sum up, the genome stays the main protagonist (i.e.…”

Cellular Plasticity in Breast Cancer Progression and Therapy

“…In this same study, an index patient demonstrated dynamic switching between mesenchymal and epithelial CTCs upon each cycle of therapy, suggesting that CTCs may maintain dynamic E/M plasticity (Yu et al, 2013;Hinohara and Polyak, 2019). This data aligns well with a recent study from Gupta and colleagues which utilized a DNA barcoding approach in the human breast cancer cell line MDA-MB-157 in order to demonstrate that distinct clonal populations of tumor cells can fluctuate between epithelial and mesenchymal states, demonstrating intrinsic E/M plasticity (Mathis et al, 2017). Additionally, they further demonstrated that progeny from a single clonal population maintain stable epithelial-to-mesenchymal ratios, suggesting that there may be an intrinsic component of distinct tumor clones which define their overall tropism for epithelial or mesenchymal states (Mathis et al, 2017).…”

In Silico implementation of evolutionary paradigm in therapy design: Towards anti-cancer therapy as Darwinian process

“…This strategy increases the long-term survival and growth of an entire lineage instead of conferring an immediate fitness benefit to one individual [36]. Based on the formal similarity of evolving cancer cell population with bacteria, viruses or yeast, it has been recently proposed that the structure of intratumor heterogeneity is an evolutionary trait which evolves towards the maximum clonal fitness at the cancer-relevant timescale in changing (or uncertain) environment and that its structure corresponds to the bet-hedging strategy [44][45][46][47] which has been recently put into therapeutic context [48].…”