An Emerging Allee Effect Is Critical for Tumor Initiation and Persistence

Tumor cells develop different strategies to cope with changing microenvironmental conditions. A prominent example is the adaptive phenotypic switching between cell migration and proliferation. While it has been shown that the migration-proliferation plasticity influences tumor spread, it remains unclear how this particular phenotypic plasticity affects overall tumor growth, in particular initiation and persistence. To address this problem, we formulate and study a mathematical model of spatio-temporal tumor dynamics which incorporates the microenvironmental influence through a local cell density dependence. Our analysis reveals that two dynamic regimes can be distinguished. If cell motility is allowed to increase with local cell density, any tumor cell population will persist in time, irrespective of its initial size. On the contrary, if cell motility is assumed to decrease with respect to local cell density, any tumor population below a certain size threshold will eventually extinguish, a fact usually termed as Allee effect in ecology. These results suggest that strategies aimed at modulating migration are worth to be explored as alternatives to those mainly focused at keeping tumor proliferation under control.Author Summary: Controlling tumor growth remains a major medical challenge. Current clinical therapies focus on strategies to reduce tumor cell proliferation. However, during tumor progression, tumor cells may switch between proliferative and migratory behaviors, thereby allowing adaptation to microenvironmental changes that result in variations in local tumor cell density. We herein explore by means of a mathematical model the impact of migration-proliferation plasticity on tumor initiation and persistence. Our work suggests that small tumors can become extinct solely by their intrinsic cell population dynamics if cell motility decreases along with local cell density. In contrast, if cell motility increases with cell density, the tumor inevitably grows. Our model suggests that the regulation of cell migration plays a key role in tumor growth as a whole, making this feature a potential target for clinical studies.