Mena invasive (Mena(INV)) promotes multicellular streaming motility and transendothelial migration in a mouse model of breast cancer

Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Journal of Cell Science (Impact Factor: 5.43). 07/2011; 124(Pt 13):2120-31. DOI: 10.1242/jcs.086231
Source: PubMed


We have shown previously that distinct Mena isoforms are expressed in invasive and migratory tumor cells in vivo and that the invasion isoform (Mena(INV)) potentiates carcinoma cell metastasis in murine models of breast cancer. However, the specific step of metastatic progression affected by this isoform and the effects on metastasis of the Mena11a isoform, expressed in primary tumor cells, are largely unknown. Here, we provide evidence that elevated Mena(INV) increases coordinated streaming motility, and enhances transendothelial migration and intravasation of tumor cells. We demonstrate that promotion of these early stages of metastasis by Mena(INV) is dependent on a macrophage-tumor cell paracrine loop. Our studies also show that increased Mena11a expression correlates with decreased expression of colony-stimulating factor 1 and a dramatically decreased ability to participate in paracrine-mediated invasion and intravasation. Our results illustrate the importance of paracrine-mediated cell streaming and intravasation on tumor cell dissemination, and demonstrate that the relative abundance of Mena(INV) and Mena11a helps to regulate these key stages of metastatic progression in breast cancer cells.

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Available from: Bojana Gligorijevic, Apr 30, 2014
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    • "PTP1B inhibition increased EGF-elicited invasion of MDA-MB231-GFP and -GFP-Mena expressing cells into collagen I gels, but had no significant effect on cells expressing Mena INV (Fig 5B). Expression of Mena INV in xenografted tumor cells decreases the concentration of EGF required for efficient chemotaxis/invasion by 25- fold in vivo (Roussos et al., 2011c); we thus asked whether PTP1B inhibition similarly increases the EGF sensitivity of invading cells in tumors. Consistent with the in vitro assays, a doseresponse analysis using the in vivo invasion assay (Wyckoff et al., 2000) on xenografts showed that PTP1B inhibition increased the sensitivity of control cells to EGF: maximal tumor cell invasion was elicited into needles containing 5nM EGF, a 5-fold lower concentration than normally required such a response (Fig 5C). "
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    ABSTRACT: During breast cancer progression, alternative mRNA splicing produces functionally distinct isoforms of Mena, an actin regulator with roles in cell migration and metastasis. Aggressive tumor cell subpopulations express Mena(INV), which promotes tumor cell invasion by potentiating EGF responses. However, the mechanism by which this occurs remains unknown. Here, we report that Mena associates constitutively with the tyrosine phosphatase PTP1B and mediates a novel negative feedback mechanism that attenuates receptor tyrosine kinase signaling. On EGF stimulation, complexes containing Mena and PTP1B are recruited to the EGFR, causing receptor dephosphorylation and leading to decreased motility responses. Mena also interacts with the 5' inositol phosphatase SHIP2, which is important for the recruitment of the Mena-PTP1B complex to EGFR. When Mena(INV) is expressed, PTP1B recruitment to EGFR is impaired, providing a mechanism for growth factor sensitization to EGF, as well as HGF and IGF, and increased resistance to EGFR and Met inhibitors in signaling and motility assays. In sum, we demonstrate that Mena plays an important role in regulating growth factor-induced signaling. Disruption of this attenuation by Mena(INV) sensitizes tumor cells to low growth factor concentrations, thereby increasing the migration and invasion responses that contribute to aggressive, malignant cell phenotypes. © 2015 by The American Society for Cell Biology.
    Full-text · Article · Sep 2015 · Molecular biology of the cell
    • "The relative abundance of MENAINV and MENA11a seems to be important to regulate key stages of the metastatic cascade in breast cancer cells. Thus, high levels of MENAINV enhance coordinated motility, transendothelial migration, and intravasation of tumor cells, promoting spontaneous lung metastases in a murine model of breast cancer [105, 106]. In contrast, increased expression of MENA11a correlates with decreased invasion, intravasation, and dissemination of cancer cells [106]. "
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    ABSTRACT: Alterations in the abundance or activities of alternative splicing regulators generate alternatively spliced variants that contribute to multiple aspects of tumor establishment, progression and resistance to therapeutic treatments. Notably, many cancer-associated genes are regulated through alternative splicing suggesting a significant role of this post-transcriptional regulatory mechanism in the production of oncogenes and tumor suppressors. Thus, the study of alternative splicing in cancer might provide a better understanding of the malignant transformation and identify novel pathways that are uniquely relevant to tumorigenesis. Understanding the molecular underpinnings of cancer-associated alternative splicing isoforms will not only help to explain many fundamental hallmarks of cancer, but will also offer unprecedented opportunities to improve the efficacy of anti-cancer treatments.
    No preview · Article · Oct 2013 · International Journal of Cell Biology
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    • "The decreased in vivo cell invasion observed in WASp À/À mice despite the presence of exogenous EGF supplied through the microneedle (Figure 3C) may appear to contradict the in vitro data indicating that EGF alone restored breast carcinoma cell invasion (Figure 4C). However, efficient chemotaxis in the tumor requires the propagation of chemotactic signals from cell to cell in a streaming fashion (Roussos et al., 2011; Sharma et al., 2012) so as to maintain the migration of cells. Consistent with this, blockade of CSF-1R in the presence of EGF was equally effective as EGFR blockade in reducing the number of invasive cells collected (Wyckoff et al., 2004). "
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    ABSTRACT: A paracrine interaction between epidermal growth factor (EGF)-secreting tumor-associated macrophages (TAMs) and colony-stimulating factor 1 (CSF-1)-secreting breast carcinoma cells promotes invasion and metastasis. Here, we show that mice deficient in the hematopoietic-cell-specific Wiskott-Aldrich syndrome protein (WASp) are unable to support TAM-dependent carcinoma cell invasion and metastasis in both orthotopic and transgenic models of mammary tumorigenesis. Motility and invasion defects of tumor cells were recapitulated ex vivo upon coculture with WASp(-/-) macrophages. Mechanistically, WASp is required for macrophages to migrate toward CSF-1-producing carcinoma cells, as well as for the release of EGF through metalloprotease-dependent shedding of EGF from the cell surface of macrophages. Our findings suggest that WASp acts to support both the migration of TAMs and the production of EGF, which in concert promote breast tumor metastasis.
    Full-text · Article · Jul 2013 · Cell Reports
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