Fibroblast activation protein drives tumor metastasis via a protease-independent role in invadopodia stabilization
Maurish Bukhari,
Navneeta Patel,
Rosa Fontana,
Miguel Santiago-Medina,
Yike Jiang,
Dongmei Li,
Kersi Pestonjamasp,
Victoria J. Christiansen,
Kenneth W. Jackson,
Patrick A. McKee,
Jing Yang
Affiliations
Maurish Bukhari
Department of Pharmacology, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA; Moores Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
Navneeta Patel
Department of Pharmacology, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA; Moores Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
Rosa Fontana
Department of Pharmacology, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA; Moores Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
Miguel Santiago-Medina
Department of Pharmacology, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA; Moores Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
Yike Jiang
Department of Pharmacology, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA; Moores Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
Dongmei Li
Department of Pharmacology, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA; Moores Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
Kersi Pestonjamasp
Moores Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
Victoria J. Christiansen
William K. Warren Medical Research Center, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Kenneth W. Jackson
William K. Warren Medical Research Center, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Patrick A. McKee
William K. Warren Medical Research Center, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Jing Yang
Department of Pharmacology, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA; Moores Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA; Corresponding author
Summary: 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.
