Fibroblast activation protein drives tumor metastasis via a protease-independent role in invadopodia stabilization

• Published in: Cell reports (Cambridge) 2023-10, Vol.42 (10), p.113302-113302, Article 113302
• Main Authors: Bukhari, Maurish, Patel, Navneeta, Fontana, Rosa, Santiago-Medina, Miguel, Jiang, Yike, Li, Dongmei, Pestonjamasp, Kersi, Christiansen, Victoria J., Jackson, Kenneth W., McKee, Patrick A., Yang, Jing
• Format: Article
• Language: English
• Subjects: breast cancer; Breast Neoplasms - pathology; Cell Line, Tumor; CP: Cancer; extracellular matrix; Extracellular Matrix - metabolism; Female; fibroblast activation protein; Fibroblasts - metabolism; Humans; invadopodia; invasion; matrix degradation; Melanoma, Cutaneous Malignant; Membrane Proteins - metabolism; MT1- MMP; Neoplasm Invasiveness - pathology; Peptide Hydrolases - metabolism; Podosomes - metabolism; Serine Endopeptidases - metabolism; tumor metastasis; TWIST1
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113302

During metastasis, tumor cells invade through the basement membrane and intravasate into blood vessels and then extravasate into distant organs to establish metastases. Here, we report a critical role of a transmembrane serine protease fibroblast activation protein (FAP) in tumor metastasis. Expression of FAP and TWIST1, a metastasis driver, is significantly correlated in several types of human carcinomas, and FAP is required for TWIST1-induced breast cancer metastasis to the lung. Mechanistically, FAP is localized at invadopodia and required for invadopodia-mediated extracellular matrix degradation independent of its proteolytic activity. Live cell imaging shows that association of invadopodia precursors with FAP at the cell membrane promotes the stabilization and growth of invadopodia precursors into mature invadopodia. Together, our study identified FAP as a functional target of TWIST1 in driving tumor metastasis via promoting invadopodia-mediated matrix degradation and uncovered a proteolytic activity-independent role of FAP in stabilizing invadopodia precursors for maturation. [Display omitted] •FAP promotes breast tumor metastasis•FAP expression is significantly correlated with TWIST1 in various human cancers•FAP is required for matrix degradation independent of its proteolytic activity•FAP localizes at invadopodia and promotes invadopodia precursor stabilization Bukhari et al. report a functional role of the transmembrane serine protease FAP in tumor metastasis. FAP is required for invadopodia-mediated matrix degradation independent of its proteolytic activity. FAP localizes at invadopodia and promotes invadopodia precursor stabilization. These results indicate a structural role of FAP at invadopodia to promote tumor metastasis.