The ability of cancer cells to migrate away from the primary tumor and colonize distant organs is the ultimate cause of mortality in cancer. Although many of the molecular and adhesion pathways have been identified, there is still no effective strategy for limiting metastasis in patients. This is in large part due to our lack of understanding of the signals that initiate cell invasion into the surrounding tissue and blood vessels. In previous work, we showed that mechanical forces from flowing interstitial fluid cause profound phenotypic changes in cancer cells. These forces are transmitted by the cell glycocalyx and influence cell migration, MMP activity and adhesion molecule expression. We propose that the glycocalyx? by virtue of its role in mechanotransduction? represents a new and promising target for inhibiting cancer migration and metastasis. In this project, we will use a tightly-integrated combination of in vitro analyses and in vivo models to determine the components and pathways responsible for mechanically-induced cell invasion, and then target these mechanisms in a mouse model of renal carcinoma.
Aim 1 a will use gene silencing to remove specific components of the glycocalyx to identify key structures involved in flow-induced activation of metastasis, and Aim 1b will examine the intracellular signaling pathways downstream of the glycocalyx that might be targeted to inhibit invasion.
In Aim 2, we will use a mouse model of renal carcinoma to determine how the glycocalyx components contribute to local intravasation into the vasculature (Aim 2a) and distant metastasis (Aim 2b). With the key glycocalyx components and targets identified, we will then use pharmacological interventions to block metastasis (Aim 2c). Finally, we will alter interstitial flow in an orthotopic mouse renal carcinoma to demonstrate the induction of metastasis by flow in the in vivo setting (Aim 3). These studies have the potential to uncover the fundamental mechanisms that initiate tumor metastasis, and will open the door to new therapeutic strategies that exploit mechanobiological signaling pathways.
The majority of cancer patient mortalities are due to metastatic disease, not growth of the primary tumor. Strategies for limiting metastasis could lead to improved clinical outcome, but are currently lacking. We propose to identify the mechanical structures and signals that initiate metastasis and then target these in a preclinical model of renal carcinoma. When complete, this project will reveal basic information about cancer mechanobiology and lead to novel strategies for treating metastatic disease.
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