Understanding and leveraging phenotypic plasticity during metastasis formation

Abstract

Cancer metastasis is the primary cause of poor prognosis and cancer-related fatalities. Metastasis formation has long been identified as a process of the detrimental systemic spread of cancer, yet cure remains a challenge. Successful metastasis formation requires tumor cells to be proliferative and invasive; however, cells cannot be effective at both tasks at the same time. Tumor cells compensate for this trade-off by changing their phenotype during metastasis formation through phenotypic plasticity. Phenotypic plasticity is a cell's ability to adopt different phenotypes stochastically or driven by environmental cues. Given the different selection pressures and competitive interactions that tumor cells face in their microenvironment, it is poorly understood how plasticity shapes the process of metastasis formation. Here, we develop an ecology-inspired mathematical model that captures stochastic phenotypic plasticity and accounts for resource competition between phenotypes. We find that phenotypically plastic tumor cell populations can drive cancer metastasis. Additionally, these populations have a stable phenotype equilibrium that maintains tumor cell heterogeneity. By modeling treatment types inspired from chemo- and immunotherapy, we also highlight that phenotypically plastic populations are protected against interventions. Turning this strength into a weakness, we corroborate current clinical practices to use this plasticity as a target for adjuvant therapy. By providing a quantitative description of a phenotypically plastic cell population and its response to interventions, we can thus achieve a better mechanistic understanding of tumor cell biology and its consequences for metastasis formation.