Endosomal WASH and exocyst complexes control exocytosis of MT1-MMP at invadopodia

J Cell Biol. 2013 Dec 23;203(6):1063-79. doi: 10.1083/jcb.201306162.

Abstract

Remodeling of the extracellular matrix by carcinoma cells during metastatic dissemination requires formation of actin-based protrusions of the plasma membrane called invadopodia, where the trans-membrane type 1 matrix metalloproteinase (MT1-MMP) accumulates. Here, we describe an interaction between the exocyst complex and the endosomal Arp2/3 activator Wiskott-Aldrich syndrome protein and Scar homolog (WASH) on MT1-MMP–containing late endosomes in invasive breast carcinoma cells. We found that WASH and exocyst are required for matrix degradation by an exocytic mechanism that involves tubular connections between MT1-MMP–positive late endosomes and the plasma membrane in contact with the matrix. This ensures focal delivery of MT1-MMP and supports pericellular matrix degradation and tumor cell invasion into different pathologically relevant matrix environments. Our data suggest a general mechanism used by tumor cells to breach the basement membrane and for invasive migration through fibrous collagen-enriched tissues surrounding the tumor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / pathology
  • Breast Neoplasms / pathology
  • Endosomes / metabolism
  • Exocytosis*
  • Extracellular Matrix / metabolism
  • Extracellular Matrix / ultrastructure
  • Female
  • Humans
  • Matrix Metalloproteinase 14 / metabolism
  • Microfilament Proteins / metabolism
  • Microfilament Proteins / physiology*
  • Models, Biological
  • Neoplasm Invasiveness
  • Neoplasm Metastasis / pathology
  • Neoplasm Metastasis / ultrastructure
  • Vesicular Transport Proteins / metabolism
  • Vesicular Transport Proteins / physiology*

Substances

  • Microfilament Proteins
  • Vesicular Transport Proteins
  • WASH protein, human
  • Matrix Metalloproteinase 14