An integrin-linked machinery of cytoskeletal regulation that enables experimental tumor initiation and metastatic colonization

Cancer Cell. 2013 Oct 14;24(4):481-98. doi: 10.1016/j.ccr.2013.08.012. Epub 2013 Sep 12.

Abstract

Recently extravasated metastatic cancer cells use the Rif/mDia2 actin-nucleating/polymerizing machinery in order to extend integrin β1-containing, filopodium-like protrusions (FLPs), which enable them to interact productively with the surrounding extracellular matrix; this process governs the initial proliferation of these cancer cells. Here, we identify the signaling pathway governing FLP lifetime, which involves integrin-linked kinase (ILK) and β-parvin, two integrin:actin-bridging proteins that block cofilin-mediated actin-filament severing. Notably, the combined actions of Rif/mDia2 and ILK/β-parvin/cofilin pathways on FLPs are required not only for metastatic outgrowth but also for primary tumor formation following experimental implantation. This provides one mechanistic explanation for how the epithelial-mesenchymal transition (EMT) program imparts tumor-initiating powers to carcinoma cells, since it enhances FLP formation through the activation of ILK/β-parvin/cofilin pathway.

Publication types

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

MeSH terms

  • Actinin / metabolism*
  • Actins / metabolism
  • Animals
  • Carcinoma / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Cytoskeleton / metabolism*
  • Epithelial-Mesenchymal Transition
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Neoplasm Metastasis
  • Neoplasms / metabolism*
  • Neoplastic Stem Cells / cytology
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Messenger / metabolism
  • Signal Transduction

Substances

  • Actins
  • PARVB protein, human
  • RNA, Messenger
  • Actinin
  • integrin-linked kinase
  • Protein-Serine-Threonine Kinases