title: CRP2, a new invadopodia actin bundling factor critically promotes breast cancer cell invasion and metastasis.
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.
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
authors.forename: Céline
authors.initials: C
authors.lastname: Hoffmann
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
authors.forename: Xianqing
authors.initials: X
authors.lastname: Mao
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.|NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
authors.forename: Monika
authors.initials: M
authors.lastname: Dieterle
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
authors.forename: Flora
authors.initials: F
authors.lastname: Moreau
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
authors.forename: Antoun
authors.initials: A
authors.lastname: Al Absi
authors.affiliation: Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
authors.forename: André
authors.initials: A
authors.lastname: Steinmetz
authors.affiliation: NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Oudin
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
authors.forename: Guy
authors.initials: G
authors.lastname: Berchem
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
authors.forename: Bassam
authors.initials: B
authors.lastname: Janji
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
authors.forename: Clément
authors.initials: C
authors.lastname: Thomas
mesh_terms: D000199:Actins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D003599:Cytoskeleton / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D060588:LIM Domain Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D000069261:Podosomes / Q000378:metabolism; D011554:Pseudopodia / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C486176:CRIP2 protein, human; D060588:LIM Domain Proteins; D020782:Matrix Metalloproteinases
keywords: LIM domain; MMP-9; actin cytoskeleton; breast cancer; invadopodia; invasion