8th Annual Symposium
Physics of Cancer
October 4-6, 2017
|PoC - Physics of Cancer - Annual Symposium|
Mechanisms of collective cell migration and the influence of the microenvironment
Institut Curie, 12 rue Lhomond, 75005 Paris, France
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Tumor invasion, the process by which carcinoma cells exit the primary tumor and enter the stroma, is one of the first steps in metastasis. This process involves a dramatic change in the microenvironment, from an epithelium encapsulated by a basement membrane to a stromal network of primarily collagen-I fibers and other ECM components, including fibronectin. Although previous studies have largely focused on dissemination of single cells in this process, it is becoming increasingly clear that in vivo, tumor cells often invade by collective migration of groups of cells. However, it is poorly understood what controls single-cell vs. collective migration in different environments and how the microvenvironment itself affects collective migration.
To address these questions, we are investigating the mechanisms of collective migration of clusters of A431 cells, a squamous cell carcinoma line, in various 2D and 3D environments in vitro. While cancer cell clusters exhibited little to no migration in isotropic 3D networks, these clusters partially spread and migrated collectively and persistently on the surface of collagen networks and at confined interfaces with collagen networks. Strikingly, clusters migrated with significantly higher persistence (along straighter paths) compared with single cells, and depending on the stiffness of the collagen network, clusters were able to migrate efficiently with or without focal adhesions. In contrast, on the surface of Matrigel, which mimics the basement membrane, clusters formed spheres with tightly apposed epithelial-like cell-cell junctions. On the surface of fibronectin or monomeric collagen, clusters spread, but cells did not migrate collectively or persistently. Localization studies by immunostaining have revealed a substrate-dependent relocalization of integrins as well as integrin- and EMT-related signaling components. Currently, we are investigating the functional roles of these components in collective cell migration. We are also investigating polarity mechanisms in migrating clusters to determine whether clusters migrate using a front "leader" cell or employ cooperative migration of many cells within the cluster. This work will advance our understanding of collective cell migration and microenvironment adaptation as well as the process of tumor invasion.