The goal of this subproject is to dissect the complex interactions between cancer cells and cells of the host microenvironment and model how these diverse interactions contribute to cancer progression and invasion, both in primary tumors and in metastasis. Tumor cells co-opt their local environment through secretion of stimulating growth factors and cytokines, recruiting stromal cells to the tumor site and promoting growth of new blood vessels. In turn, the locally activated host microenvironment provides growth factors and matrix degrading enzymes to modify the proliferation and invasion of the tumor cells. Currently, our understanding of the complex and reciprocal interplay between the tumor and host cells is limited, particularly with regard to the diversity of metastatic tissue microenvironments that can be colonized by cancer cells. We aim to address this significant knowledge gap by combining innovative experimental and computational approaches that ultimately should revolutionize our understanding and treatment of primary cancers and metastases.