The CD44s splice isoform is a central mediator for invadopodia activity

J Cell Sci. 2016 Apr 1;129(7):1355-65. doi: 10.1242/jcs.171959. Epub 2016 Feb 11.


The ability for tumor cells to spread and metastasize to distant organs requires proteolytic degradation of extracellular matrix (ECM). This activity is mediated by invadopodia, actin-rich membrane protrusions that are enriched for proteases. However, the mechanisms underlying invadopodia activity are not fully understood. Here, we report that a specific CD44 splice isoform, CD44s, is an integral component in invadopodia. We show that CD44s, but not another splice isoform CD44v, is localized in invadopodia. Small hairpin (sh)RNA-mediated depletion of CD44s abolishes invadopodia activity, prevents matrix degradation and decreases tumor cell invasiveness. Our results suggest that CD44s promotes cortactin phosphorylation and recruits MT1-MMP (also known as MMP14) to sites of matrix degradation, which are important activities for invadopodia function. Importantly, we show that depletion of CD44s inhibits breast cancer cell metastasis to the lung in animals. These findings suggest a crucial mechanism underlying the role of the CD44s splice isoform in breast cancer metastasis.

Keywords: Breast cancer; CD44s; Invadopodia; Metastasis; Splice isoform.

Publication types

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

MeSH terms

  • Animals
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cortactin / metabolism
  • Female
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism*
  • Lung Neoplasms / secondary*
  • MCF-7 Cells
  • Matrix Metalloproteinase 14 / metabolism
  • Mice
  • Mice, Nude
  • NIH 3T3 Cells
  • Neoplasm Invasiveness / genetics
  • Neoplasm Invasiveness / pathology*
  • Neoplasm Transplantation
  • Phosphorylation / genetics
  • Podosomes / metabolism*
  • Protein Isoforms / genetics
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Transplantation, Heterologous


  • CD44 protein, human
  • Cortactin
  • Hyaluronan Receptors
  • Protein Isoforms
  • RNA, Small Interfering
  • Matrix Metalloproteinase 14