UC San Diego

Tumor metastasis, the leading cause of death among cancer patients, is a complex multi-step process during which tumor cells disseminate from their primary site to distant organs. The transcription factor Twist1 is overexpressed in many aggressive human cancers and is a potent inducer of tumor metastasis. Mechanistically, Twist1 activates a developmental program known as the Epithelial-Mesenchymal Transition (EMT), during which carcinoma cells lose cell- cell junctions and become more migratory and invasive. Twist1 can also induce the formation of invadopodia, actin -rich membrane protrusions that recruit various proteases to degrade the extracellular matrix (ECM). Various studies show that invadopodia are crucial for tumor invasion during metastasis. We have identified the membrane- associated serine protease Fibroblast Activation Protein (FAP) to be a critical gene induced upon Twist1 activation to promote invadopodia function. However, the precise role of FAP at invadopodia and its function in tumor metastasis is not well understood. This study presents data demonstrating that FAP is essential for invadopodia- mediated ECM degradation and breast tumor metastasis in vivo. Mechanistically, I found that FAP is required for the proper localization of matrix metalloproteinase MT1- MMP to invadopodia in order to generate mature and functional invadopodia for EMT degradation. Together, these results indicate that FAP is a critical regulator of invadopodia function and tumor metastasis. Given the unique expression of FAP in human cancers, FAP could be a promising target for anti-metastasis therapeutics