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Extracellular Matrix Control of Breast Cancer Metastasis and Dormancy

Abstract
To metastasize, a cell must travel through circulation to a secondary tissue, and this process causes 90% of all cancer deaths. Although inefficient, metastasis is not random, and only capable seeds in hospitable soils are capable of outgrowing into detectable metastases. The overall hypothesis in this work is that the secondary tissue microenvironment, particularly the extracellular matrix (ECM), mediates metastasis. We posit that the ability of metastatic cells to survive dormancy, exit quiescence, and colonize a tissue depends upon the ability of the soil to sustain survival, and subsequently trigger outgrowth. We created a simple biomaterial platform with systematic control over the ECM protein density and composition to determine if integrin binding governs how metastatic cells differentiate between secondary tissues. Instead of examining individual behaviors, we compiled large patterns of phenotypes associated with adhesion to and migration on these controlled ECMs. In combining this novel analysis with a simple biomaterial platform, we created an in vitro fingerprint that is predictive of in vivo aggressive integrin-mediated metastasis in live cells and in patient data. We propose that this predictive approach is much simpler, faster, and more economical than complex 3D biomaterials or mouse models. However, approximately two-thirds of all breast cancer deaths occur after the five-year survival mark, and many patients develop metastatic disease several years after remission. In these patients, tumor cells have disseminated, survived, but remained dormant, before outgrowing into a metastatic lesion. When inducing dormancy in vitro via mitogen withdrawal, we have found that both a capable seed and a hospitable soil are required for sustained quiescence. Collagen is required for early survival, and long-term latency requires remodeling the extracellular matrix and creation of a rich, organized fibronectin matrix, which mediates survival through sustained adhesion and activation of ERK signaling. This survival mechanism can be enhanced by local stromal cells, which are recruited by the tumor cells to assemble extremely dense fibronectin matrices. Together, this work suggests that both a competent seed and a proper soil are required for metastasis, and emphasizes the dynamic changes in the microenvironment that can promote survival and growth of disseminated tumor cells.
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