Biochemistry and Molecular Biology Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN.
Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
J Cell Biol. 2019 Jan 7;218(1):317-332. doi: 10.1083/jcb.201802032. Epub 2018 Nov 28.
The process by which tumor cells mechanically invade through surrounding stroma into peripheral tissues is an essential component of metastatic dissemination. The directed recruitment of the metalloproteinase MT1-MMP to invadopodia plays a critical role in this invasive process. Here, we provide mechanistic insight into MT1-MMP cytoplasmic tail binding protein 1 (MTCBP-1) with respect to invadopodia formation, matrix remodeling, and invasion by pancreatic tumor cells. MTCBP-1 localizes to invadopodia and interacts with MT1-MMP. We find that this interaction displaces MT1-MMP from invadopodia, thereby attenuating their number and function and reducing the capacity of tumor cells to degrade matrix. Further, we observe an inverse correlation between MTCBP-1 and MT1-MMP expression both in cultured cell lines and human pancreatic tumors. Consistently, MTCBP-1-expressing cells show decreased ability to invade in vitro and metastasize in vivo. These findings implicate MTCBP-1 as an inhibitor of the metastatic process.
肿瘤细胞通过周围基质机械性浸润到周围组织的过程是转移扩散的一个重要组成部分。金属蛋白酶 MT1-MMP 被定向募集到入侵伪足中，在这个浸润过程中起着关键作用。在这里，我们提供了关于 MT1-MMP 细胞质尾结合蛋白 1（MTCBP-1）与入侵伪足形成、基质重塑和胰腺肿瘤细胞浸润相关的机制见解。MTCBP-1 定位于入侵伪足并与 MT1-MMP 相互作用。我们发现这种相互作用将 MT1-MMP 从入侵伪足中置换出来，从而减少了它们的数量和功能，并降低了肿瘤细胞降解基质的能力。此外，我们在培养的细胞系和人胰腺肿瘤中观察到 MTCBP-1 和 MT1-MMP 表达之间存在反比关系。一致地，表达 MTCBP-1 的细胞在体外侵袭能力和体内转移能力下降。这些发现表明 MTCBP-1 是转移过程的抑制剂。
