PDF(Pubmed)
Abstract：
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.
摘要：
在转移过程中，肿瘤细胞通过基底膜侵入并进入血管，然后外渗到远处器官以建立转移。这里,我们报道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。转移驱动因子FAP和TWIST1的表达，在几种类型的人类癌症中显著相关，TWIST1诱导的乳腺癌转移到肺部需要FAP。机械上,FAP位于侵染足中，并且是侵染足中介导的细胞外基质降解所必需的，与其蛋白水解活性无关。活细胞成像表明，侵袭足前体在细胞膜上与FAP的结合可促进侵袭足前体向成熟侵袭足中的稳定和生长。一起,我们的研究将FAP确定为TWIST1的功能靶标,通过促进侵袭足病介导的基质降解来驱动肿瘤转移,并揭示了FAP在稳定侵袭足病前体以促进成熟方面的蛋白水解活性非依赖性作用.
