Project Summary The majority of breast cancer related deaths occur as a result of metastasis. Once the cancer cells metastasize, the 5-year relative survival rate for breast cancer patients drastically drops. During metastasis, a complex series of events is initiated by changes in the extracellular matrix (ECM) composition and architecture in distant tissues, where the metastatic cancer cells take root and form secondary tumors. These distinct changes in the premetastatic niche (PMN) facilitate tumor cell colonization, phenotypic heterogeneity of the cell population, and contribute to drug resistance frequently observed in metastatic tumors. Using an engineered model of the PMN, we have demonstrated that extracellular vesicles (EVs) facilitate dynamic changes in premetastatic tissues, and that blocking key events during PMN formation disrupts the metastatic process. Our preliminary studies indicate that ECM proteins transglutaminase 2 (TG2) and fibronectin (FN) play a significant role in establishing the PMN through an EV-dependent mechanism. However, fundamental gaps remain in identifying critical events within the niche that facilitate metastatic colonization of tumor cells, cellular plasticity, and drug resistance. The overall goal of this proposal is to identify how the dynamic changes within the metastatic niche make the distant tissues hospitable to metastatic cancer cells. Aim 1 will use our novel model of the PMN to identify how specific changes in the PMN facilitate colonization by disseminating cells. Aim 2 is focused on isolating specific effects of ECM dynamics and cellular constituents within the PMN that impact phenotypic heterogeneity and immunogenicity, giving rise to growth permissive and grow restrictive environments. Aim 3 will identify mechanisms by which key matrix components within the niche protect metastatic tumor cells from therapeutic agents. Our cross-disciplinary team encompasses expertise in biomedical engineering, metastasis, imaging, and EV biology. The proposed studies will establish novel mechanisms by which the PMN facilitates breast cancer metastasis, an essential step towards successful treatments to disrupt the metastatic process.

Project Narrative During metastasis, evidence suggests that tumor derived extracellular vesicles facilitate metastasis by initiating changes in the cellular constituents and extracellular matrix of the future metastatic site, resulting in the development of the premetastatic niche. Our goal is to utilize our engineered model of the premetastatic niche to determine the role that matrix dynamics, cellular compositions, and cellular plasticity have on metastatic colonization and drug resistance. These data will be critical for the development of novel therapies designed to treat the most lethal aspect of breast cancer.