Pancreatic tumor cell metastasis is restricted by MT1-MMP binding protein MTCBP-1

J Cell Biol. 2019 Jan 7;218(1):317-332. doi: 10.1083/jcb.201802032. Epub 2018 Nov 28.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Dioxygenases / antagonists & inhibitors
  • Dioxygenases / genetics*
  • Dioxygenases / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Intestinal Neoplasms / genetics*
  • Intestinal Neoplasms / metabolism
  • Intestinal Neoplasms / mortality
  • Intestinal Neoplasms / secondary
  • Intestine, Small / metabolism
  • Intestine, Small / pathology
  • Lymphatic Metastasis
  • Matrix Metalloproteinase 14 / genetics*
  • Matrix Metalloproteinase 14 / metabolism
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness
  • Pancreas / metabolism
  • Pancreas / pathology
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / pathology
  • Podosomes / genetics*
  • Podosomes / metabolism
  • Podosomes / pathology
  • Protein Binding
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Survival Analysis
  • Xenograft Model Antitumor Assays

Substances

  • RNA, Small Interfering
  • ADI1 protein, human
  • Dioxygenases
  • MMP14 protein, human
  • Matrix Metalloproteinase 14