Mathematical modeling of metabolism rewiring in cancer eco-evolution and metastasis tropism

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SUMMARY It is critically important to establish the causes of organ-specific metastasis; without this knowledge, prevention and timely treatment of metastatic cancer will likely remain limited. This application aims to develop novel mathematical models to understand how a rewired cellular metabolism enables cancer cells that originate in one organ such as the breast to colonize distal organs such as the lung, the brain, and the bone, which have distinct microenvironments. We will study metabolic rewiring in parental cells and their metastatic derivatives and ask how metabolic gradients in the primary tumor can generate and maintain diverse lineages with specific metabolic adaptations for organ-specific metastasis. Our central hypotheses are 1) that metabolic adaptations are key to the match between the seed (the disseminated cell) and the soil (the distal site) in metastatic breast cancer, and 2) that the metabolic microenvironment in a primary tumor drives metabolically diverse subpopulations. The hypotheses have been formulated based on 1) published data detailing metabolic heterogeneity and that metabolic adaptations can promote metastasis, 2) preliminary data and analysis of RNA expression, metabolomics, and flux measurements, revealing different metabolic adaptations in breast tumor cells that home to different tissues, and 3) preliminary data showing that metastatic lineages respond differently to hypoxia and nutrient gradients, indicating a role for the metabolic microenvironment in maintaining diverse subpopulations within the same heterogeneous primary tumor. Mathematical modeling is critical to integrate experimental data and infer changes in metabolic fluxes that cannot be directly measured. The application proposes a research strategy that combines experimental, clinical, and mathematical analysis to identify new vulnerabilities in metastatic cancer cells. We will also develop novel mathematical models to study the ecological interactions between cell lines and their microenvironment and determine the conditions that lead to coexistence of metabolically distinct pre-metastatic subpopulations in the primary tumor.