Fibroblast Activation Protein-Alpha, a Serine protease that Facilitates Metastasis by Modification of Diverse Microenvironments

Our overarching hypothesis is that FAP functions with other proteases in an extracellular communication network to digest certain proteins, thereby exposing signals stored in peptide regions that enable breast cancer cells to thrive in diverse microenvironments. FAP likely has important functions in two parts of the metastatic cascade 1 FAP and proteases such as MMP-1 and MMP-9 cooperate to produce fragments of ECM proteins during adjacent tissue remodeling and these derivative peptides promote fibroblast growth, ECM deposition and angiogenesis 2 cancer cell membrane FAP cleaves precursive A2AP to generate the more effective derivative for protecting and stabilizing fibrin within ECM margins of the expanding neoplastic cell mass as well as fibrin within cancer cellfibrinplatelet emboli that lead to hematogenous metastasis. We believe that peptides that target and inhibit FAP on FAP-expressing cells can be produced by taking advantage of the substrateactive-site binding specificity of FAP. This progress report documents the initial experiments and preparation of cell lines needed to complete the aims of the project. Substantial progress has been made and has resulted in production of 1 manuscript, 1 abstract presented at an international meeting, and three grant proposals one of which was funded and another still pending.