Abstract
Evolutionary dynamics allows us to understand many changes happening in a broad variety of biological systems, ranging from individuals to complete ecosystems. It is also behind a number of remarkable organizational changes that happen during the natural history of cancers. These reflect tumour heterogeneity, which is present at all cellular levels, including the genome, proteome and phenome, shaping its development and interrelation with its environment. An intriguing observation in different cohorts of oncological patients is that tumours exhibit an increased proliferation as the disease progresses, while the timescales involved are apparently too short for the fixation of sufficient driver mutations to promote explosive growth. Here, we discuss how phenotypic plasticity, emerging from a single genotype, may play a key role and provide a ground for a continuous acceleration of the proliferation rate of clonal populations with time. We address this question by combining the analysis of real-time growth of non-small-cell lung carcinoma cells (N-H460) together with stochastic and deterministic mathematical models that capture proliferation trait heterogeneity in clonal populations to elucidate the contribution of phenotypic transitions on tumour growth dynamics.
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Code Availability
Simulations were conducted in MATLAB (version R2020a). Code files for the discrete model simulations and experimental data are publicly accessible at https://github.com/molabEvoDynamics/rep_StochasticFluctuationsDriveNonGeneticEvolution.
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Acknowledgements
Authors thank Juan Jiménez Sánchez and Jesús Bosque Martínez (Universidad de Castilla-La Mancha, Spain) for their fruitful feedback on this work. We also thank Juan Antonio Delgado (Universidad de Murcia, Spain) for kindly sharing his broad knowledge on translational evolutionary theory with us through valuable discussions.
Funding
This work was supported by the James S. McDonnell Foundation (Collaborative award 220020450, doi: 10.37717/220020560), Junta de Comunidades de Castilla-La Mancha (Grants SBPLY/17/180501/000154 and SBPLY/19/180501/000211), Ministerio de Ciencia e Innovación MCIN/AEI/10.13039/501100011033 (grant PID2019-110895RB-I00) and Asociación Española Contra el Cáncer (Grant 2019-PRED-28372).
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GFC and VMP-G formulated the hypothesis and designed the research. JD, AP-R and MP conceived and performed the experiments. GFC, CO-S and VMP-G performed the numerical simulations and statistical analyses. GFC carried out the analytical study. CO-S, GFC and VMP-G wrote the paper. All authors gave final approval for publication.
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Ortega-Sabater, C., F. Calvo, G., Dinić, J. et al. Stochastic Fluctuations Drive Non-genetic Evolution of Proliferation in Clonal Cancer Cell Populations. Bull Math Biol 85, 8 (2023). https://doi.org/10.1007/s11538-022-01113-4
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DOI: https://doi.org/10.1007/s11538-022-01113-4