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Abrupt transitions to tumor extinction: a phenotypic quasispecies model

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Abstract

The dynamics of heterogeneous tumor cell populations competing with healthy cells is an important topic in cancer research with deep implications in biomedicine. Multitude of theoretical and computational models have addressed this issue, especially focusing on the nature of the transitions governing tumor clearance as some relevant model parameters are tuned. In this contribution, we analyze a mathematical model of unstable tumor progression using the quasispecies framework. Our aim is to define a minimal model incorporating the dynamics of competition between healthy cells and a heterogeneous population of cancer cell phenotypes involving changes in replication-related genes (i.e., proto-oncogenes and tumor suppressor genes), in genes responsible for genomic stability, and in house-keeping genes. Such mutations or loss of genes result into different phenotypes with increased proliferation rates and/or increased genomic instabilities. Despite bifurcations in the classical deterministic quasispecies model are typically given by smooth, continuous shifts (i.e., transcritical bifurcations), we here identify a novel type of bifurcation causing an abrupt transition to tumor extinction. Such a bifurcation, named as trans-heteroclinic, is characterized by the exchange of stability between two distant fixed points (that do not collide) involving tumor persistence and tumor clearance. The increase of mutation and/or the decrease of the replication rate of tumor cells involves this catastrophic shift of tumor cell populations. The transient times near bifurcation thresholds are also characterized, showing a power law dependence of exponent \(-1\) of the transients as mutation is changed near the bifurcation value. These results are discussed in the context of targeted cancer therapy as a possible therapeutic strategy to force a catastrophic shift by simultaneously delivering mutagenic and cytotoxic drugs inside tumor cells.

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Acknowledgments

We thank the members of the Complex Systems Lab for their helpful comments, as well as the members of the Institute of Evolutionary Biology (IBE) for their critics and comments. The authors acknowledge the computing facilities of the Dynamical Systems Group (Universitat de Barcelona). This article was partially funded by the Botín Foundation (JS, RVS), by the Spanish grant FIS2012-39288 (RVS), by the Santa Fe Institute (RVS), by the Spanish Secretaria de Estado de Investigación, Desarrollo e Innovación grants MTM2013-41168-P (CS, RM), and by grant 2014-SGR-1145 from the Catalan government (CS, RM). This work has also counted with the support of Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya.

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Authors and Affiliations

  1. ICREA-Complex Systems Lab, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain

    Josep Sardanyés & Ricard Solé

  2. Institut de Biologia Evolutiva, CSIC-Universitat Pompeu Fabra, Barcelona, Spain

    Josep Sardanyés & Ricard Solé

  3. Departament de Matemàtiques, Edifici C. Facultat de Ciències, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain

    Regina Martínez

  4. Departament de Matemàtiques i Informàtica, Universitat de Barcelona, Barcelona, Spain

    Carles Simó

  5. The Santa Fe Institute, Santa Fe, New Mexico, USA

    Ricard Solé

Authors
  1. Josep Sardanyés
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  2. Regina Martínez
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  3. Carles Simó
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  4. Ricard Solé
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Correspondence to Josep Sardanyés.

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Sardanyés, J., Martínez, R., Simó, C. et al. Abrupt transitions to tumor extinction: a phenotypic quasispecies model. J. Math. Biol. 74, 1589–1609 (2017). https://doi.org/10.1007/s00285-016-1062-9

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  • DOI: https://doi.org/10.1007/s00285-016-1062-9

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