成纤维细胞激活蛋白通过在侵袭伪足稳定中的独立于蛋白酶的作用来驱动肿瘤转移。
Fibroblast activation protein drives tumor metastasis via a protease-independent role in invadopodia stabilization.
发表日期：2023 Oct 19
作者：
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
来源：
Cell Reports
摘要：
在转移过程中，肿瘤细胞侵入基底膜并渗入血管，然后渗出到远处器官以形成转移。在这里，我们报告了跨膜丝氨酸蛋白酶成纤维细胞激活蛋白（FAP）在肿瘤转移中的关键作用。 FAP 和 TWIST1（一种转移驱动因素）的表达在多种类型的人类癌症中显着相关，并且 FAP 是 TWIST1 诱导的乳腺癌肺转移所必需的。从机制上讲，FAP 定位于侵袭伪足，并且是侵袭伪足介导的细胞外基质降解所必需的，与其蛋白水解活性无关。活细胞成像显示，侵袭伪足前体与细胞膜上的 FAP 的结合促进了侵袭伪足前体的稳定和生长，成为成熟的侵袭伪足。总之，我们的研究确定了 FAP 作为 TWIST1 的功能靶点，通过促进侵袭伪足介导的基质降解来驱动肿瘤转移，并揭示了 FAP 在稳定侵袭伪足前体成熟方面的独立于蛋白水解活性的作用。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。
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.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.