Chapter 17 - Toward an Ultimate Explanation of Intratumor Heterogeneity

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Abstract

While it is widely acknowledged that intratumor heterogeneity is mostly generated by genomic instability, we propose that genomic instability is only part of a proximate mechanism that maintains intratumor heterogeneity through oncogenic selection. Within tissues and organs, malignant cells achieve greater success by cooperating in the process of tumor construction, rather than by just being in isolation. This process would involve the selection of a bet-hedging strategy during oncogenesis to generate the diversity of cell components needed to build, de novo, such an intricate cooperative system. This process requires sufficient time to generate the diversity of relevant clones, which may explain why solid tumors tend to occur late in life. In liquid environments, opportunities for structurally complex tumors are more limited. This may help explain why cancer cells from liquid tumors generally do not aggregate, are on average less heterogeneous (i.e., low selection for bet-hedging), and can be detrimental early in life (e.g., leukemia). In an evolutionary context, this suggests that the bet-hedging strategy is not only a universal risk-diversification strategy that evolves in the populations which face uncertain future and/or environment, it is also selected when there is a need of building, de novo, cooperative and complex systems.

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    2020, Journal of Theoretical Biology
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    This strategy increases the long-term survival and growth of an entire lineage instead of conferring an immediate fitness benefit to one individual (Carja and Plotkin, 2017). 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 (Chisholm et al., 2016; Nichol et al., 2016; Gravenmier et al., 2018; Thomas et al., 2017) which has been recently put into therapeutic context (Mathis et al., 2017). Distinguishing between the intratumor heterogeneity due to the differences in the DNA sequences and that resulting from the epigenetic modifications is instructive for the biological insight as well as for the ’physical’ realization of an eventual therapy.

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

    2018, Physics Letters, Section A: General, Atomic and Solid State Physics
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    In bacteria, the well known risk-diversification strategy evolved in the populations when facing uncertain future and/or environment [13–15] 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 cancer-relevant timescale in changing (or uncertain) environment and that its structure corresponds to the bet-hedging strategy [18–22] which has been recently put into therapeutic context [23,24]. To sum up, the genome stays the main protagonist (i.e. selection unit) in the evolution of cancer cells, nevertheless with non-genetic heterogeneity of its eventual clone being the crucial adaptive trait at cancer-relevant, instead of proximate timescale.

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