The majority of cancer mortality arises because tumors cells leave their primary site, giving rise to metastatic tumors in other organs. While there are many and complex biologic aspects of tumor progression leading to cancer metastasis, local invasion through the basement membrane of epithelia and migration of primary tumor cells through the extracellular matrix (ECM) to access lymphatic and vascular channels is clearly a critical early step. Tumor cells can invade and migrate individually or as groups. Accumulating pathologic and in vivo experimental evidence now indicates that the most common form of tumor cell migration is likely as a collective group. While we have learned a great deal about the cell biologic, biochemical, and biophysical mechanisms underlying the migration of individual cells in 2D, 3D and in vivo, our understanding about the regulation of collective cell migration in cancer metastasis is at an early stage. Organization of cells into collective groups and their migration of cells is governed by a number of forces: passive (elastic and adhesive forces), frictional (resistance to cells sliding past one another and cells sliding across a substrate), active (protrusive and contractile forces), and traction forces upon the underlying or surrounding ECM. Which forces are critical for the collective migration of tumor cells, and how, is not understood. The overarching hypothesis of this proposal is that cell-ECM and cell-cell interactions will combine through adhesion crosstalk to modulate tumor collective cell migration by altering cooperativity of motion and force generation. To test this hypothesis we have developed computational tools and 2D and in vivo 3D experimental models that measure various physical forces within and around a group of tumor cells as they organize to migrate in a collective through the tumor stroma and within the tumor epithelium. Our approach to the problem is iterative: using computational simulations to inform experimental testing of how various forces contribute to the organization and motion of collective groups of tumor cells. We propose four specific aims using these tools to address this problem:
Aim 1. To determine an integrated experimental and computational model of how tumor cell-intrinsic changes in adhesion influence collective migration.
Aim 2. To determine how changes in the tumor environment affect collective migration of tumor cell.
Aim 3. To determine how cell-cell and cell-ECM forces influence the nature of tumor cell collective migration in clinically relevant primary human breast tumor samples.
Aim 4. To develop a computational model of collective cell migration dynamics in tissues.
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