For metastasis to occur, cancer cells must successfully leave the primary tumor and invade into the surrounding tissue to gain entry into the circulatory system. Cancer cells accomplish this migration and invasion by degrading both neighboring tissues and blood vessels. Specialized structures formed by cancer cells known as invadopodia mediate this invasive behavior. Invadopodia project outwards from the surface of cancer cells and contain many enzymes that cleave tissues. High invadopodia formation and enzymatic activity are associated with increased metastasis and poor clinical outcome. Furthermore, as metastasis is the primary reason for mortality of cancer patients, research into inhibiting invadopodia could lead to a significant reduction in cancer mortality. Given the essential role of invadopodia in tumor metastasis, inhibition of invadopodia-mediated tissue degradation would be an effective way to block tumor cell invasion and metastasis. To achieve this goal, it is critical to understand the molecular components and regulatory machineries of invadopodia. Considerable research has gone into examining the proteins that regulate the cytoskeleton of invadopodia. However, in addition to these modulatory proteins, there exist other proteins at invadopodia with unknown functions. Recent studies have also begun to suggest that invadopodia enzymes may also provide a structural role in invadopodia formation. Indeed, one such protein present at invadopodia whose function still remains unknown is the tissue enzyme Fibroblast Activation Protein (FAP). This proposal is centered on understanding the mechanism by which FAP regulates invadopodia and subsequent tumor cell invasion and metastasis. Understanding the mechanisms that regulate tissue degradation and cell invasion will give rise to new anti- metastasis therapies that target tumor cell dissemination rather than proliferation. This proposal will test the hypothesis that FAP regulates tumor cell invasion and metastasis through invadopodia-mediated tissue degradation. This hypothesis will be tested using a variety of approaches in three specific aims.
In Aim 1, the dynamics of FAP localization to invadopodia will be assessed in various cancer cell subtypes.
In Aim 2, the proteins that interact with and dock FAP to invadopodia will be elucidated. Lastly, in Aim 3, the in vivo role of FAP in tumor progression and metastasis will be determined.
Cancer cells metastasize by forming invasive structures that degrade and breach tissues known as invadopodia. This proposal is focused on understanding how Fibroblast Activation Protein (FAP) regulates invadopodia-mediated cell invasion. As metastasis is the primary reason for mortality of cancer patients, research into understanding invadopodia formation and function is of the essence.
|Eckert, Mark A; Santiago-Medina, Miguel; Lwin, Thinzar M et al. (2017) ADAM12 induction by Twist1 promotes tumor invasion and metastasis via regulation of invadopodia and focal adhesions. J Cell Sci 130:2036-2048|