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Prostate cancer (PCa) cells interact with the stroma and extracellular matrix (ECM) during tumor expansion and invasion during metastasis. Dissecting the complex matrix-cancer interplay is essential to halting tumor progression. A vital component of the ECM is perlecan/heparan sulfate proteoglycan 2 (HSPG2). As a large extracellular proteoglycan, perlecan helps orchestrate tumor angiogenesis, proliferation, differentiation and invasion. Actively metastasizing cancer cells must proteolytically degrade several tissue borders which perlecan patrols, including the basement membrane, vasculature, reactive stromal matrix and bone marrow. We have demonstrated that perlecan, even fully decorated with glycosaminoglycan chains and in the context of the basement membrane, is cleaved efficiently by the protease matrilysin/matrix metalloproteinase 7 (MMP-7). MMP-7 levels increase, especially in relation to its endogenous inhibitor, during metastatic programming in several cancers including PCa. Recent analysis of a tissue microarray of 157 prostatectomy patients showed perlecan and MMP-7 are increased in tandem, with perlecan disappearing at the sites where MMP-7 is high, indicative of a protease-substrate relationship in tissue. This idea is supported by the finding that perlecan fragments are present in serum of PCa patients, with a majority from domain IV. Additionally, higher perlecan staining in cancer related stroma positively correlated with higher grade cancer. Investigating the effects of perlecan on metastatic PCa cells showed full length perlecan and specifically domain IV of perlecan triggers clustering of PCa cells. Perlecan proteolysis by MMP-7 reverses this, favoring cell dispersion and tumor dyscohesion. To discover the molecular signaling events associated with perlecan binding to PCa cells, a reverse phase protein array was analyzed for protein interactions that were plotted in Cytoscape. Network analysis revealed, and western blotting confirmed, perlecan and MMP-7 mediated proteolysis altered focal adhesion kinase (FAK) signaling, with intact perlecan and domain IV suppressing FAK activity during clustering, and MMP-7 cleaved perlecan activating FAK, consistent with the induction of dispersion. Further work showed that cleavage of perlecan increased the pro-cancer transcription factor forkhead box protein M1 (FOXM1). This work reveals that degradation of perlecan by MMP-7 in the tumor microenvironment can unlock stable epithelial contacts and reprogram PCa cells for invasion and metastasis through processes involving FAK and FoxM1. Citation Format: Brian J. Grindel, Jerahme Martinez, Hamim Zafar, Luay K. Nakhleh, Leland W.K. Chung, Mary C. Farach-Carson. Interplay between perlecan/HSPG2 and matrilysin/MMP-7 in the prostate cancer tumor microenvironment directs metastatic programming through focal adhesion kinase and FoxM1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1563.