Cancer Cell Invasion and the Epithelial-Mesenchymal Transition
The dissemination of tumor cells to distant organs during metastasis is responsible for over 90% of cancer-related fatalities. Tumor cells utilize a variety of phenotypes to escape the primary tumor microenvironment, including individual and collective (group) migration. It has been hypothesized that the scattering and dissemination of tumor cells may arise from a phenotypic transformation known as the epithelial-mesenchymal transition (EMT). Classically, EMT is associated with the complete loss of epithelial traits (strong cell-cell adhesion and limited motility), with the acquisition of mesenchymal characteristics (minimal cell-cell adhesion and fast motility). Moreover, EMT pathways are associated with increased resistance to stress and apoptosis. Thus, EMT may generate specific subpopulations that are disproportionately invasive, resistant to apoptosis and drive tumor progression. We will characterize these emergent behaviors using single cell tracking in engineered microenvironments to explore the role of heterogeneity and plasticity. We will further perturb these invasion dynamics using drugs to motivate new therapeutic strategies.
Engineered Cell-Materials Interfaces
Tumors are often identified clinically as rigid masses within softer tissues. This rigidity arises from changes in the mechanics and microstructure of the local extracellular matrix as disease progression occurs. We will use micropatterning and 3D printing of soft materials to build well-defined microenvironments in vitro. These will be used to systematically interrogate the role of the cell-materials interface in driving malignant phenotypes such as drug resistance and proliferation. (Image from Weaver et al. Curr Opin Cell Biol, 2010)
Designed 3D Tumor Architectures
Malignant tumors often display distinct subpopulations arranged with complex spatial organization. In collaboration with Jeff Morgan (Brown), we use directed self-assembly to build microtissues with well-defined composition and architecture. The morphogenesis of these 3D tumors will be investigated with single cell resolution to elucidate patterns of cooperation and competition between subpopulations, particularly in hostile microenvironments. These tumors may be further implanted in vivo to characterize angiogenesis, circulating tumor cells and metastasis.