Endophilin A2 Promotes TNBC Cell Invasion and Tumor Metastasis

Baldassarre, Tomas; Watt, Kathleen; Truesdell, Peter; Meens, Jalna; Schneider, M.; Sengupta, Sandip; Craig, Andrew W.B.

doi:10.1158/1541-7786.mcr-14-0573

Cited by 18 publications

(29 citation statements)

References 57 publications

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“…It was previously demonstrated that these cholesterol-rich PM microdomains contain MT1-MMP (Annabi et al, 2001;Galvez, 2003). It was proposed that in HT1080 fibrosarcoma cells, MT1-MMP endocytosis is controlled by several clathrin-dependent and -independent endocytic pathways (Baldassarre et al, 2015;Remacle et al, 2003). Although caveolae might interfere with MT1-MMPdependent ECM degradation in MDA-MB-231 cells (Yamaguchi et al, 2009), their direct role in MT1-MMP uptake is unlikely, and they might be involved in membrane and invadopodia organization and in sensing the mechanical stress encountered by tumor cells during invasion (Parton and del Pozo, 2013;Yamaguchi et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

MT1-MMP targeting to endolysosomes is mediated by upregulation of flotillins

Planchon

Morris

Genest

et al. 2018

Journal of Cell Science

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Tumor cell invasion and metastasis formation are the major cause of death in cancer patients. These processes rely on extracellular matrix (ECM) degradation mediated by organelles termed invadopodia, to which the transmembrane matrix metalloproteinase MT1-MMP (also known as MMP14) is delivered from its reservoir, the RAB7-containing endolysosomes. How MT1-MMP is targeted to endolysosomes remains to be elucidated. Flotillin-1 and -2 are upregulated in many invasive cancers. Here, we show that flotillin upregulation triggers a general mechanism, common to carcinoma and sarcoma, which promotes RAB5-dependent MT1-MMP endocytosis and its delivery to RAB7-positive endolysosomal reservoirs. Conversely, flotillin knockdown in invasive cancer cells greatly reduces MT1-MMP accumulation in endolysosomes, its subsequent exocytosis at invadopodia, ECM degradation and cell invasion. Our results demonstrate that flotillin upregulation is necessary and sufficient to promote epithelial and mesenchymal cancer cell invasion and ECM degradation by controlling MT1-MMP endocytosis and delivery to the endolysosomal recycling compartment.

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Section: Discussionmentioning

confidence: 99%

MT1-MMP targeting to endolysosomes is mediated by upregulation of flotillins

Planchon

Morris

Genest

et al. 2018

Journal of Cell Science

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“…The stable silencing of MMP-14 was carried out using a pLKO.1 lentiviral construct encoding an shRNA targeting human MMP-14 from the TRC library (Dharmacon). Lentiviral production in transfected HEK293 cells, and the transduction and selection of MDA-MB-231 and MDA-Src were performed as previously described [ 34 ]. The extent of MMP-14 KD was evaluated by immunoblot with an MMP-14 antibody (Abcam).…”

Section: Methodsmentioning

confidence: 99%

“…MDA-MB-231 cells were treated with or without Fab 3369 or IgG 3369 at the indicated doses upon seeding on coverslips coated with TRITC-labeled thin gelatin for 18 hours, as previously described [ 34 ]. Degradation spots from epifluorescence micrographs were scored using imaging software (Image ProPlus).…”

Section: Methodsmentioning

confidence: 99%

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A novel immunotherapy targeting MMP-14 limits hypoxia, immune suppression and metastasis in triple-negative breast cancer models

et al. 2017

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Matrix metalloproteinase-14 (MMP-14) is a clinically relevant target in metastatic cancers due to its role in tumor progression and metastasis. Since active MMP-14 is localized on the cell surface, it is amenable to antibody-mediated blockade in cancer, and here we describe our efforts to develop novel inhibitory anti-MMP-14 antibodies. A phage-displayed synthetic humanized Fab library was screened against the extracellular domain of MMP-14 and a panel of MMP14-specific Fabs were identified. A lead antibody that inhibits the catalytic domain of MMP-14 (Fab 3369) was identified and treatment of MDA-MB-231 breast cancer cells with Fab 3369 led to significant loss of extracellular matrix degradation and cell invasion abilities. In mammary orthotopic tumor xenograft assays, MMP-14 blockade by IgG 3369 limited tumor growth and metastasis. Analysis of tumor tissue sections revealed that MMP-14 blockade limited tumor neoangiogenesis and hypoxia. Similar effects of MMP-14 blockade in syngeneic 4T1 mammary tumors were observed, along with increased detection of cytotoxic immune cell markers. In conclusion, we show that immunotherapies targeting MMP-14 can limit immune suppression, tumor progression, and metastasis in triple-negative breast cancer.

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“…Previous studies have determined that Endo II plays an important role in cancer biology [ 17 , 21 ]. We have previously reported that Endo II promotes growth, invasion, and metastasis in triple-negative breast cancer (TNBC) models [ 22 ]. There are currently no studies exploring the role of Endo II in HER2+ breast cancer, or its effects on response to treatment with trastuzumab.…”

Section: Introductionmentioning

confidence: 99%

Endophilin A2 promotes HER2 internalization and sensitivity to trastuzumab-based therapy in HER2-positive breast cancers

2017

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BackgroundHuman epidermal growth factor receptor-2 (HER2) is amplified and a clinical target in a subset of human breast cancers with high rates of metastasis. Targeted therapies involving the antibody trastuzumab and trastuzumab-emtansine (T-DM1) have greatly improved outcomes for HER2-positive (HER2+) breast cancer patients. However, resistance to these targeted therapies can develop and limit their efficacy. Here, we test the involvement of the endocytic adaptor protein endophilin A2 (Endo II) in HER2+ breast cancer models, and their responses to treatments with trastuzumab and T-DM1.MethodsEndo II expression in human breast tumors and lymph node metastases were analyzed by immunohistochemistry. Stable silencing of Endo II was achieved in HER2+ cancer cell lines (SK-BR-3 and HCC1954) to test Endo II effects on HER2 levels, localization and signaling, cell motility and tumor metastasis. The effects of Endo II silencing on the responses of HER2+ cancer cells to trastuzumab or T-DM1 treatments were tested using real-time cell motility and cytotoxicity assays.ResultsHigh Endo II protein expression was detected in HER2-positive tumors, and was linked to worse overall survival in node-positive HER2+ breast cancers at the mRNA level. Stable silencing of Endo II in HER2+ cell lines led to elevated levels of HER2 on the cell surface, impaired epidermal growth factor-induced HER2 internalization, and reduced signaling to downstream effector kinases Akt and Erk. Endo II silencing also led to decreased migration and invasion of HER2+ cancer cells in vitro, and impaired lung seeding following tail vein injection in mice. In addition, Endo II silencing also impaired HER2 internalization in response to Trastuzumab, and led to reduced cytotoxicity response in HER2+ cancer cells treated with T-DM1.ConclusionsOur study provides novel evidence of Endo II function in HER2+ cancer cell motility and trafficking of HER2 that relates to effective treatments with trastuzumab or T-DM1. Thus, differential expression of Endo II may relate to sensitivity or resistance to trastuzumab-based therapies for HER2+ cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0900-z) contains supplementary material, which is available to authorized users.

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Endophilin A2 Promotes TNBC Cell Invasion and Tumor Metastasis

Cited by 18 publications

References 57 publications

MT1-MMP targeting to endolysosomes is mediated by upregulation of flotillins

MT1-MMP targeting to endolysosomes is mediated by upregulation of flotillins

A novel immunotherapy targeting MMP-14 limits hypoxia, immune suppression and metastasis in triple-negative breast cancer models

Endophilin A2 promotes HER2 internalization and sensitivity to trastuzumab-based therapy in HER2-positive breast cancers

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