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Metastasis is the leading cause of fatality for women diagnosed with breast cancer. The most common anatomical sites of distant tumor growth include the brain, lung, liver, and bone, and it is well known that this metastatic spread in breast cancer is not random. Rather, different subtypes of breast cancer exhibit unique patterns of metastatic site preference. Given the physical and chemical diversity of these secondary tissue sites, my lab hypothesizes that there is a relationship between the biophysical and biochemical properties of the tissue, and the ability of cells within a particular subtype of breast cancer to adhere, migrate, grow, and respond to chemotherapy at these secondary sites. We create biomaterial microenvironments, which capture some of the key physical and biochemical elements of these tissues (brain, lung, and bone). From a large screen of many breast cancer cell lines against designer ECM matrices, we found that collagen I can support entrance into a dormant-like phenotype during serum deprivation, but long-term survival (4-8 weeks) requires the creation of a rich, organized fibronectin matrix generated via cell tension through ROCK. Cell lines incapable of creating this fibronectin ECM cannot survive these long periods of dormancy, and successful survival appears to critically depend on creation of this matrix via α5 integrin, and adhesion via αv integrin binding and ERK activation. The fibronectin matrix can be created by the latent cancer cells themselves, or by local stromal cells (fibroblasts and mesenchymal stem cells) recruited via TGFβ. Most striking for potential therapeutic intervention, cancer cell outgrowth after dormant culture requires MMP2-mediated fibronectin disassembly. I will discuss these findings, and how we can use rational material design to identify new, more powerful drug regimens to kill cancer cells more efficiently.
Department of Chemical Engineering, University of Massachusetts, Amherst
12:00 pm at Van Andel Institute
Conference Room 3104/3105
For questions, please contact Kim Cousineau at 616.234.5684.