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Syntaxin4-Munc18c Interaction Promotes Breast Tumor Invasion and Metastasis by Regulating MT1-MMP Trafficking
Invasion of neighboring extracellular matrix (ECM) by malignant tumor cells is a hallmark of metastatic progression. This invasion can be mediated by subcellular structures known as invadopodia, the function of which depends upon soluble N-ethylmaleimide-sensitive factor-activating protein receptor...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9306282/ https://www.ncbi.nlm.nih.gov/pubmed/34876482 http://dx.doi.org/10.1158/1541-7786.MCR-20-0527 |
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author | Brasher, Megan I. Chafe, Shawn C. McDonald, Paul C. Nemirovsky, Oksana Gorshtein, Genya Gerbec, Zachary J. Brown, Wells S. Grafinger, Olivia R. Marchment, Matthew Matus, Esther Dedhar, Shoukat Coppolino, Marc G. |
author_facet | Brasher, Megan I. Chafe, Shawn C. McDonald, Paul C. Nemirovsky, Oksana Gorshtein, Genya Gerbec, Zachary J. Brown, Wells S. Grafinger, Olivia R. Marchment, Matthew Matus, Esther Dedhar, Shoukat Coppolino, Marc G. |
author_sort | Brasher, Megan I. |
collection | PubMed |
description | Invasion of neighboring extracellular matrix (ECM) by malignant tumor cells is a hallmark of metastatic progression. This invasion can be mediated by subcellular structures known as invadopodia, the function of which depends upon soluble N-ethylmaleimide-sensitive factor-activating protein receptor (SNARE)-mediated vesicular transport of cellular cargo. Recently, it has been shown the SNARE Syntaxin4 (Stx4) mediates trafficking of membrane type 1–matrix metalloproteinase (MT1-MMP) to invadopodia, and that Stx4 is regulated by Munc18c in this context. Here, it is observed that expression of a construct derived from the N-terminus of Stx4, which interferes with Stx4-Munc18c interaction, leads to perturbed trafficking of MT1-MMP, and reduced invadopodium-based invasion in vitro, in models of triple-negative breast cancer (TNBC). Expression of Stx4 N-terminus also led to increased survival and markedly reduced metastatic burden in multiple TNBC models in vivo. The findings are the first demonstration that disrupting Stx4-Munc18c interaction can dramatically alter metastatic progression in vivo, and suggest that this interaction warrants further investigation as a potential therapeutic target. IMPLICATIONS: Disrupting the interaction of Syntaxin4 and Munc18c may be a useful approach to perturb trafficking of MT1-MMP and reduce metastatic potential of breast cancers. |
format | Online Article Text |
id | pubmed-9306282 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-93062822023-01-05 Syntaxin4-Munc18c Interaction Promotes Breast Tumor Invasion and Metastasis by Regulating MT1-MMP Trafficking Brasher, Megan I. Chafe, Shawn C. McDonald, Paul C. Nemirovsky, Oksana Gorshtein, Genya Gerbec, Zachary J. Brown, Wells S. Grafinger, Olivia R. Marchment, Matthew Matus, Esther Dedhar, Shoukat Coppolino, Marc G. Mol Cancer Res New Horizons in Cancer Biology Invasion of neighboring extracellular matrix (ECM) by malignant tumor cells is a hallmark of metastatic progression. This invasion can be mediated by subcellular structures known as invadopodia, the function of which depends upon soluble N-ethylmaleimide-sensitive factor-activating protein receptor (SNARE)-mediated vesicular transport of cellular cargo. Recently, it has been shown the SNARE Syntaxin4 (Stx4) mediates trafficking of membrane type 1–matrix metalloproteinase (MT1-MMP) to invadopodia, and that Stx4 is regulated by Munc18c in this context. Here, it is observed that expression of a construct derived from the N-terminus of Stx4, which interferes with Stx4-Munc18c interaction, leads to perturbed trafficking of MT1-MMP, and reduced invadopodium-based invasion in vitro, in models of triple-negative breast cancer (TNBC). Expression of Stx4 N-terminus also led to increased survival and markedly reduced metastatic burden in multiple TNBC models in vivo. The findings are the first demonstration that disrupting Stx4-Munc18c interaction can dramatically alter metastatic progression in vivo, and suggest that this interaction warrants further investigation as a potential therapeutic target. IMPLICATIONS: Disrupting the interaction of Syntaxin4 and Munc18c may be a useful approach to perturb trafficking of MT1-MMP and reduce metastatic potential of breast cancers. American Association for Cancer Research 2022-03-01 2022-03-03 /pmc/articles/PMC9306282/ /pubmed/34876482 http://dx.doi.org/10.1158/1541-7786.MCR-20-0527 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs International 4.0 License. |
spellingShingle | New Horizons in Cancer Biology Brasher, Megan I. Chafe, Shawn C. McDonald, Paul C. Nemirovsky, Oksana Gorshtein, Genya Gerbec, Zachary J. Brown, Wells S. Grafinger, Olivia R. Marchment, Matthew Matus, Esther Dedhar, Shoukat Coppolino, Marc G. Syntaxin4-Munc18c Interaction Promotes Breast Tumor Invasion and Metastasis by Regulating MT1-MMP Trafficking |
title | Syntaxin4-Munc18c Interaction Promotes Breast Tumor Invasion and Metastasis by Regulating MT1-MMP Trafficking |
title_full | Syntaxin4-Munc18c Interaction Promotes Breast Tumor Invasion and Metastasis by Regulating MT1-MMP Trafficking |
title_fullStr | Syntaxin4-Munc18c Interaction Promotes Breast Tumor Invasion and Metastasis by Regulating MT1-MMP Trafficking |
title_full_unstemmed | Syntaxin4-Munc18c Interaction Promotes Breast Tumor Invasion and Metastasis by Regulating MT1-MMP Trafficking |
title_short | Syntaxin4-Munc18c Interaction Promotes Breast Tumor Invasion and Metastasis by Regulating MT1-MMP Trafficking |
title_sort | syntaxin4-munc18c interaction promotes breast tumor invasion and metastasis by regulating mt1-mmp trafficking |
topic | New Horizons in Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9306282/ https://www.ncbi.nlm.nih.gov/pubmed/34876482 http://dx.doi.org/10.1158/1541-7786.MCR-20-0527 |
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