Modeling the tumor microenvironment as a complex ecosystem

Abstract

The tumor microenvironment is a complex ecosystem composed of diverse cell types engaged in heterogeneous interactions. At a coarse-grained level, however, these interactions, while heterogeneous, are not totally random: tumor, stromal, and immune populations can often be organized into two opposing ecological communities, namely pro-tumor and anti-tumor teams. Members within the same team tend to interact cooperatively, whereas members of opposite teams interact antagonistically. In the first part of this thesis, we develop a structured two team statistical-physics framework that captures this interaction heterogeneity while remaining analytically tractable. Using this approach, we characterize the dynamical phases of such two-team ecosystems, including regimes in which one community excludes the other and regimes in which both communities coexist. A further layer of complexity arises from phenotypic plasticity: cells in the tumor microen- vironment can switch phenotypes through epigenetic reprogramming, thereby altering their ecological roles. In the second part of this thesis, we investigate the ecological consequences of phenotypic switching, beginning with the dynamics of two competing species and extending to large ecosystems in the thermodynamic limit. We show that phenotypic switching can qualitatively alter ecological outcomes, including stability and coexistence. Finally, metabolic interactions are a major driver of tumor progression in the tumor microenvironment. In the third part of this thesis, we study the ecological consequences of tumor metabolic reprogramming using a consumer-resource framework. Our results suggest that the Warburg effect can be understood as a strategy of niche construction, through which tumors reshape their metabolic environment in ways that promote persistence and progression.