Scales of Cancer Evolution: Selfish Genome or Cooperating Cells?

Abstract

The exploitation of the evolutionary modus operandi of cancer to steer its progression towards drug sensitive cancer cells is a challenging research topic. Integrating evolutionary principles into cancer therapy requires properly identified selection level, the relevant timescale, and the respective fitness of the principal selection unit on that timescale. Interpretation of some features of cancer progression, such as increased heterogeneity of isogenic cancer cells, is difficult from the most straightforward evolutionary view with the cancer cell as the principal selection unit. In the paper, the relation between the two levels of intratumour heterogeneity, genetic, due to genetic instability, and non-genetic, due to phenotypic plasticity, is reviewed and the evolutionary role of the latter is outlined. In analogy to the evolutionary optimization in a changing environment, the cell state dynamics in cancer clones are interpreted as the risk diversifying strategy bet hedging, optimizing the balance between the exploitation and exploration of the cell state space.

The two sides of chromosomal instability: drivers and brakes in cancer

“…This strategy, known as biological bet-hedging or "not putting all your eggs in one basket", allows tumor cells to diversify their phenotypes, spreading the risk and increasing the likelihood of some cells to survive under selective pressures, such as those imposed by anti-tumor drug treatments. 23,407,408 Moreover, Ippolito et al previously reported the link between CIN and drug resistance through the upregulation of ATP binding cassette subfamily G member 2 (ABCG2), a drug efflux pump, due to the amplification of its upstream regulator MAPK13 in topotecanresistant tumor cells generated from treatment using CIN-inducing drug nocodazole. 17 Together, these show that CIN fuels genomic diversity, upon which selection works, leading to the development of drug resistance.…”

Leveraging Cancer Phenotypic Plasticity for Novel Treatment Strategies

“…The idea that phenotypic plasticity and non-genetic mechanisms play important roles in cancer, including metastasis and drug resistance, was suggested a decade ago [ 54 ], and is now well supported by several lines of experimental evidence [ 57 , 63 , 64 , 65 ]. In fact, it is now clear that phenotypic plasticity and non-genetic mechanisms are not only critical but are also leveraged as a bet-hedging strategy in cancer [ 47 , 66 , 67 , 68 , 69 ]. Furthermore, the realization that phenotypic plasticity and non-genetic mechanisms can also account for a “persister” population contributing to drug resistance in cancer further underscores their importance in the disease pathology [ 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 ].…”

Clinical implications of lncRNA LINC-PINT in cancer

“…Cancer cells exhibit variability formally termed tumor heterogeneity, and this is a well-known explanation behind the failure of cancer therapy where resistant cells selectively survive repeated drug treatments (Brutovsky, 2022;Mahinfar et al, 2022). Contributing to this problem is also the lack of suitable diagnostic, therapeutic and prognostic biomarkers (Najafi, 2022).…”