Metastasis accounts for the vast majority of cancer-related deaths but its underlying mechanisms are incompletely understood. During tumor progression extensive remodeling of the tumor microenvironment occurs and facilitates metastasis. In particular, linearization of collagen, one of the most abundant extracellular matrix (ECM) proteins in tumors, is recognized as a hallmark of aggressive breast cancers and is associated with poor prognosis. At the cellular level, bundles of linearized collagen facilitate tumor cell invasion and metastasis by providing tracks on which tumor cells can easily migrate. Cell-generated mechanical tension has been proposed to contribute to collagen remodeling, but it remained unknown whether this is the sole mechanism by which collagen linearization is established or whether other mechanisms also play prominent roles in this process. Our recent studies revealed that cancer cells secrete factors that can linearize collagen independently of cell-generated mechanical forces. Specifically, we found that the tumor cell-secreted factor WISP1 (CCN4) promotes collagen linearization, tumor cell invasion and metastasis. However, the cellular and molecular mechanisms by which WISP1 linearizes collagen and promote metastasis remain incompletely understood. To uncover these mechanisms we will 1) define the specific steps of the metastatic cascade that are impacted by WISP1, 2) determine the molecular mechanisms by which WISP1 regulates collagen linearization and promotes tumor cell invasion, and 3) test therapeutic modalities to block WISP1?s function and prevent metastasis. This will be achieved by performing detailed analyses of breast cancer progression and metastasis in mouse models and in vitro invasion assays. Central to our studies is also the use of scanning electron microscopy and intravital multiphoton fluorescence and second harmonic generation microscopy to visualize alterations in ECM architecture in vitro and in vivo. Globally, these studies will elucidate fundamental mechanisms of collagen fiber linearization and test innovative therapeutic approaches to limit metastasis by normalizing collagen architecture.
Collagen linearization in breast tumors is a key pathogenic event that leads to enhanced tumor cell invasion and metastasis, and to poor prognosis. However, despite its recognized clinical prognostic value, little is known about the mechanisms responsible for collagen linearization. This project will determine the function of novel secreted regulators of collagen linearization and test whether they could be exploited to normalize collagen architecture in tumors and as anti-metastasis therapy.
