CRP2, a new invadopodia actin bundling factor critically promotes breast cancer cell invasion and metastasis
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Céline Hoffmann1,*, Xianqing Mao1,*, Monika Dieterle1,2, Flora Moreau1, Antoun Al Absi1, André Steinmetz3, Anaïs Oudin2, Guy Berchem1, Bassam Janji1 and Clément Thomas1
1 Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
2 NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
3 Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
* These authors have contributed equally to this work
Clément Thomas, email:
Keywords: actin cytoskeleton, breast cancer, invadopodia, invasion, LIM domain, MMP-9
Received: October 26, 2015 Accepted: January 27, 2016 Published: February 11, 2016
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.
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