Metastasis-suppressor NME1 controls the invasive switch of breast cancer by regulating MT1-MMP surface clearance

CATALINA LODILLINSKY ; LAETITIA FUHRMANN ; MARIE IRONDELLE ; OLENA PYLYPENKO ; XIAO-YAN LI 1; HÉLÈNE BONSANG-KITZIS ; FABIEN REYA ; SOPHIE VACHER ; CLAIRE CALMEL ; SANDRA ANTOINE ; OLIVIER DE WEVER ; IVAN BIÈCHE ; MARIE-LISE LACOMBE ; ANA MARIA EIJAN; ANNE HOUDUSSE ; ANNE VINCENT-SALOMON ; STEPHEN J. WEISS ; PHILIPPE CHAVRIER ; MATHIEU BOISSAN

Simposio; BUENOS AIRES BREAST CANCER SYMPOSIUM 2021; 2021

Metastasis-suppressor NME1 controls the invasive switch of breast cancer by regulating MT1-MMP surface clearanceCatalina Lodillinsky1,2, Laetitia Fuhrmann3, Marie Irondelle4, Olena Pylypenko4, Xiao-Yan Li5, Hélène Bonsang-Kitzis6,7,¶, Fabien Reyal6,7, Sophie Vacher8, Claire Calmel9, Sandra Antoine4, Olivier De Wever10, Ivan Bièche8, Marie-Lise Lacombe9, Ana Maria Eiján1,2, Anne Houdusse4, Anne Vincent-Salomon3, Stephen J. Weiss5, Philippe Chavrier4 and Mathieu Boissan9,111 Research Area, Instituto de Oncología Ángel H. Roffo, Universidad de Buenos Aires, Buenos Aires, Argentina2 Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina3 Institut Curie, PSL Research University, Diagnostic and Theranostic Medicine Division, Paris, France4 Institut Curie, PSL Research University, CNRS UMR144, Paris, France5 Division of Medical Genetics, Department of Internal Medicine, Life Sciences Institute, University of Michigan, Ann Arbor MI, USA6 Department of Surgery, Institut Curie, Paris, France7 Translational Research Department, RT2Lab Team, INSERM U932, Immunity and Cancer, Institut Curie, Paris, France8 Pharmacogenomic Unit, Institut Curie, Paris, France9 University Sorbonne, INSERM UMR_S 938, Saint-Antoine Research Center, CRSA, Paris, France10 Laboratory of Experimental Cancer Research, Cancer Research Institute Ghent (CRIG), Department of Human Structure and Repair, Ghent University, Ghent, Belgium11 Laboratory of Biochemistry and Hormonology, Tenon Hospital, AP-HP, Paris, France  AbstractMembrane 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.