Metastasis-suppressor NME1 controls the invasive switch of breast cancer by regulating MT1-MMP surface clearance
Year: 2021
Type: article
Abstract: Membrane Type 1 Matrix Metalloprotease (MT1-MMP) contributes to the invasive progression of breast cancers by degrading extracellular matrix tissues. Nucleoside diphosphate kinase, NME1/NM23-H1, has been identified as a metastasis suppressor; however, its contribution to local invasion in breast cancer is not known. Here, we report that NME1 is up-regulated in ductal carcinoma in situ (DCIS) as compared to normal breast epithelial tissues. NME1 levels drop in microinvasive and invasive components of breast tumor cells relative to synchronous DCIS foci. We find a strong anti-correlation between NME1 and plasma membrane MT1-MMP levels in the invasive components of breast tumors, particularly in aggressive histological grade III and triple-negative breast cancers. Knockout of NME1 accelerates the invasive transition of breast tumors in the intraductal xenograft model. At the mechanistic level, we find that MT1-MMP, NME1 and dynamin-2, a GTPase known to require GTP production by NME1 for its membrane fission activity in the endocytic pathway, interact in clathrin-coated vesicles at the plasma membrane. Loss of NME1 function increases MT1-MMP surface levels by inhibiting endocytic clearance. As a consequence, the ECM degradation and invasive potentials of breast cancer cells are enhanced. This study identifies the down-modulation of NME1 as a potent driver of the in situ-to invasive transition during breast cancer progression.
Source: Oncogene
Authors: Catalina Lodillinsky, Laetitia Fuhrmann, Marie Irondelle, Olena Pylypenko, Xiao-Yan Li, Hélène Bonsang-Kitzis, Fabien Reyal, Sophie Vacher, Claire Calmel, Olivier De Wever, Ivan Bièche, Marie-Lise Lacombe, Ana Maria Eiján, Anne Houdusse, Anne Vincent-Salomon, Stephen J. Weiss, Philippe Chavrier, Mathieu Boissan
Institutions: Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, Université Paris Sciences et Lettres, Institut Curie, Centre National de la Recherche Scientifique, Biologie cellulaire et Cancer, University of Michigan, Michigan Medicine, Inserm, Immunité et Cancer, Ramsay Santé Hôpital privé des Peupliers, Sorbonne Université, Centre de Recherche Saint-Antoine, Ghent University, Cancer Research Institute Ghent, Assistance Publique – Hôpitaux de Paris, Hôpital Tenon
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,990
Funders: Breast Cancer Research Foundation, University of Michigan, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation ARC pour la Recherche sur le Cancer, Centre National de la Recherche Scientifique, Groupement des Entreprises Françaises dans la lutte contre le Cancer, National Institutes of Health, Rogel Cancer Center, University of Michigan, National Cancer Institute
Awards: G1519688000, G2450198060, G2730293317, G2817673831, G381665449, G496050054, Function of Membrane Type Matrix Metalloproteinase, G7240651115, G7777646733, G8234668411, Développment d'une infrastructure française distribuée coordonnée, G889950262, G8916787474, G9000207620, University of Michigan Rogel Cancer Center Support Grant 2023-2028
OpenAlex ID: W3161454284