Hypoxia-resistance heterogeneity in tumours: the impact of geometrical characterization of environmental niches and evolutionary trade-offs. A mathematical approach

In the study of cancer evolution and therapeutic strategies, scientific evidence shows that a key dynamics lies in the tumor-environment interaction. In particular, oxygen concentration plays a central role in the determination of the phenotypic heterogeneity of cancer cell populations, whose qualitative and geometric characteristics are predominant factors in the occurrence of relapses and failure of eradication. We propose a mathematical model able to describe the eco-evolutionary spatial dynamics of tumour cells in their adaptation to hypoxic microenvironments. As a main novelty with respect to the existing literature, we combine a phenotypic indicator reflecting the experimentally-observed metabolic trade-off between the hypoxia-resistance ability and the proliferative potential with a 2d geometric domain, without the constraint of radial symmetry. The model is settled in the mathematical framework of phenotype-structured population dynamics and it is formulated in terms of systems of coupled non-linear integro-differential equations. The computational outcomes demonstrate that hypoxia-induced selection results in a geometric characterization of phenotypic-defined tumour niches that impact on tumour aggressiveness and invasive ability. Furthermore, results show how the knowledge of environmental characteristics provides a predictive advantage on tumour mass development in terms of size, shape, and composition

Hypoxia-related radiotherapy resistance in tumours: treatment efficacy investigation in an eco-evolutionary perspective

In the study of therapeutic strategies for the treatment of cancer, eco-evolutionary dynamics are of particular interest, since characteristics of the tumour population, interaction with the environment and effects of the treatment, influence the geometric and epigenetic characterization of the tumour with direct consequences on the efficacy of the therapy and possible relapses. In particular, when considering radiotherapy, oxygen concentration plays a central role both in determining the effectiveness of the treatment and the selective pressure due to hypoxia. We propose a mathematical model, settled in the framework of epigenetically-structured population dynamics and formulated in terms of systems of coupled non-linear integro-differential equations, that aims to catch these phenomena and to provide a predictive tool for the tumour mass evolution and therapeutic effects. The outcomes of the simulations show how the model is able to explain the impact of environmental selection and therapies on the evolution of the mass, motivating observed dynamics such as relapses and therapeutic failures. Furthermore it offers a first hint for the development of therapies which can be adapted to overcome problems of resistance and relapses