Predictive experiment-based multiscale models of angiogenesis in breast cancer

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DESCRIPTION (provided by applicant): This research will focus on triple-negative breast cancer (TNBC), which is highly metastatic, has the worst prognosis among breast cancer subtypes, and is lacking effective therapies. Interactions between different cell types in the tumor microenvironment and metastatic niches are determinants of metastatic progression. In particular, tumor angiogenesis plays an important role since tumors require blood supply to grow and metastasize. A quantitative understanding of the complexity of these interactions is presently lacking. To achieve a better understanding of these processes, the development of predictive experiment-based molecular-detailed computational models of tumor growth and metastasis is necessary. The long-term goal of this project is to develop experiment-based mechanistic models of breast cancer and apply them to modeling therapeutic interventions. Specifically, we will use experimental and computational approaches to: (1) investigate key angiogenic factors, cytokines and chemokines in the progression of breast tumors to metastases; (2) investigate the characteristics of lung metastasis, the most common site for TNBC metastases; (3) test anti-metastatic agents by targeting selective cytokines, angiogenic factors and chemokines. The computational developments will be tightly coupled to the cutting-edge imaging techniques at the molecular, cellular, microvascular, and tissue levels. Invasive human breast cancer cell lines will be used to generate orthotopic xenografts in the mammary fat pad of female mice. The measurements will include the characterization and localization of receptor and ligand expression for a wide range of molecules of the VEGF family together with selected cytokines and chemokines at different stages of tumor growth and metastasis, such as interleukin-6 and CCL5; temporal and spatial development of hypoxia and microvasculature in growing tumors, and functional characteristics of the tumor vasculature and interstitium, e.g. blood volume, vascular permeability, diffusive transport in the tumor extracellular matrix (ECM). Immunohistochemistry and 3D microscopy will be used to characterize lung metastases. Part of these data will serve as the input to computational models and part used for model validation. Several therapeutic, anti-metastatic agents targeting selective cytokines, chemokines and angiogenic factors will be used, and their molecular interactions and transport will be modeled using ordinary differential equation-based compartmental models, three-dimensional partial differential equation-based models, agent-based models, and hybrid models. The research will contribute to a fundamental understanding of breast cancer biology, to the identification of therapeutic targets and biomarkers, and to a quantitative interpretation of clinical data. The synergistic combination of computational and experimental studies will provide significant insights into metastatic TNBC.