CRP2, a new invadopodia actin bundling factor critically promotes breast cancer cell invasion and metastasis

Céline Hoffmann, Xianqing Mao, Monika Dieterle, Flora Moreau, Antoun Al Absi, André Steinmetz, Anaïs Oudin, Guy Berchem, Bassam Janji, Clément Thomas*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

24 Citations (Scopus)

Abstract

A critical process underlying cancer metastasis is the acquisition by tumor cells of an invasive phenotype. At the subcellular level, invasion is facilitated by actin-rich protrusions termed invadopodia, which direct extracellular matrix (ECM) degradation. Here, we report the identification of a new cytoskeletal component of breast cancer cell invadopodia, namely cysteine-rich protein 2 (CRP2). We found that CRP2 was not or only weakly expressed in epithelial breast cancer cells whereas it was up-regulated in mesenchymal/invasive breast cancer cells. In addition, high expression of the CRP2 encoding gene CSRP2 was associated with significantly increased risk of metastasis in basal-like breast cancer patients. CRP2 knockdown significantly reduced the invasive potential of aggressive breast cancer cells, whereas it did not impair 2D cell migration. In keeping with this, CRP2-depleted breast cancer cells exhibited a reduced capacity to promote ECM degradation, and to secrete and express MMP-9, a matrix metalloproteinase repeatedly associated with cancer progression and metastasis. In turn, ectopic expression of CRP2 in weakly invasive cells was sufficient to stimulate cell invasion. Both GFP-fused and endogenous CRP2 localized to the extended actin core of invadopodia, a structure primarily made of actin bundles. Purified recombinant CRP2 autonomously crosslinked actin filaments into thick bundles, suggesting that CRP2 contributes to the formation/maintenance of the actin core. Finally, CRP2 depletion significantly reduced the incidence of lung metastatic lesions in two xenograft mouse models of breast cancer. Collectively, our data identify CRP2 as a new cytoskeletal component of invadopodia that critically promotes breast cancer cell invasion and metastasis.

Original languageEnglish
Pages (from-to)13688-13705
Number of pages18
JournalOncotarget
Volume7
Issue number12
DOIs
Publication statusPublished - 22 Mar 2016

Keywords

  • Actin cytoskeleton
  • Breast cancer
  • Invadopodia
  • Invasion
  • LIM domain
  • MMP-9

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