BMC Biology (Oct 2021)
The mitochondrially-localized nucleoside diphosphate kinase D (NME4) is a novel metastasis suppressor
- Marie-Lise Lacombe,
- Frederic Lamarche,
- Olivier De Wever,
- Teresita Padilla-Benavides,
- Alyssa Carlson,
- Imran Khan,
- Anda Huna,
- Sophie Vacher,
- Claire Calmel,
- Céline Desbourdes,
- Cécile Cottet-Rousselle,
- Isabelle Hininger-Favier,
- Stéphane Attia,
- Béatrice Nawrocki-Raby,
- Joël Raingeaud,
- Christelle Machon,
- Jérôme Guitton,
- Morgane Le Gall,
- Guilhem Clary,
- Cedric Broussard,
- Philippe Chafey,
- Patrice Thérond,
- David Bernard,
- Eric Fontaine,
- Malgorzata Tokarska-Schlattner,
- Patricia Steeg,
- Ivan Bièche,
- Uwe Schlattner,
- Mathieu Boissan
Affiliations
- Marie-Lise Lacombe
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA
- Frederic Lamarche
- Université Grenoble Alpes, INSERM U1055, Laboratory of Fundamental and Applied Bioenergetics (LBFA), and SFR Environmental and Systems Biology (BEeSy)
- Olivier De Wever
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Cancer Research Institute Ghent (CRIG), Ghent University
- Teresita Padilla-Benavides
- Molecular Biology and Biochemistry Department, Wesleyan University
- Alyssa Carlson
- Molecular Biology and Biochemistry Department, Wesleyan University
- Imran Khan
- Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute
- Anda Huna
- Cancer Research Center of Lyon, INSERM U1052, CNRS UMR 5286, Léon Bérard Center, Lyon University
- Sophie Vacher
- Unit of Pharmacogenetics, Department of Genetics, Curie Institute
- Claire Calmel
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA
- Céline Desbourdes
- Université Grenoble Alpes, INSERM U1055, Laboratory of Fundamental and Applied Bioenergetics (LBFA), and SFR Environmental and Systems Biology (BEeSy)
- Cécile Cottet-Rousselle
- Université Grenoble Alpes, INSERM U1055, Laboratory of Fundamental and Applied Bioenergetics (LBFA), and SFR Environmental and Systems Biology (BEeSy)
- Isabelle Hininger-Favier
- Université Grenoble Alpes, INSERM U1055, Laboratory of Fundamental and Applied Bioenergetics (LBFA), and SFR Environmental and Systems Biology (BEeSy)
- Stéphane Attia
- Université Grenoble Alpes, INSERM U1055, Laboratory of Fundamental and Applied Bioenergetics (LBFA), and SFR Environmental and Systems Biology (BEeSy)
- Béatrice Nawrocki-Raby
- Reims Champagne Ardenne University, INSERM, P3Cell UMR-S 1250, SFR CAP-SANTE
- Joël Raingeaud
- INSERM U1279, Gustave Roussy Institute
- Christelle Machon
- Cancer Research Center of Lyon, INSERM U1052, CNRS UMR 5286, Léon Bérard Center, Lyon University
- Jérôme Guitton
- Cancer Research Center of Lyon, INSERM U1052, CNRS UMR 5286, Léon Bérard Center, Lyon University
- Morgane Le Gall
- Proteomics Platform 3P5, Paris University, Cochin Institute, INSERM, U1016, CNRS, UMR8104
- Guilhem Clary
- Proteomics Platform 3P5, Paris University, Cochin Institute, INSERM, U1016, CNRS, UMR8104
- Cedric Broussard
- Proteomics Platform 3P5, Paris University, Cochin Institute, INSERM, U1016, CNRS, UMR8104
- Philippe Chafey
- Proteomics Platform 3P5, Paris University, Cochin Institute, INSERM, U1016, CNRS, UMR8104
- Patrice Thérond
- AP-HP, CHU Bicêtre, Laboratory of Biochemistry, Le Kremlin-Bicêtre Hospital
- David Bernard
- Cancer Research Center of Lyon, INSERM U1052, CNRS UMR 5286, Léon Bérard Center, Lyon University
- Eric Fontaine
- Université Grenoble Alpes, INSERM U1055, Laboratory of Fundamental and Applied Bioenergetics (LBFA), and SFR Environmental and Systems Biology (BEeSy)
- Malgorzata Tokarska-Schlattner
- Université Grenoble Alpes, INSERM U1055, Laboratory of Fundamental and Applied Bioenergetics (LBFA), and SFR Environmental and Systems Biology (BEeSy)
- Patricia Steeg
- Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute
- Ivan Bièche
- Unit of Pharmacogenetics, Department of Genetics, Curie Institute
- Uwe Schlattner
- Université Grenoble Alpes, INSERM U1055, Laboratory of Fundamental and Applied Bioenergetics (LBFA), Institut Universitaire de France (IUF)
- Mathieu Boissan
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA
- DOI
- https://doi.org/10.1186/s12915-021-01155-5
- Journal volume & issue
-
Vol. 19,
no. 1
pp. 1 – 29
Abstract
Abstract Background Mitochondrial nucleoside diphosphate kinase (NDPK-D, NME4, NM23-H4) is a multifunctional enzyme mainly localized in the intermembrane space, bound to the inner membrane. Results We constructed loss-of-function mutants of NDPK-D, lacking either NDP kinase activity or membrane interaction and expressed mutants or wild-type protein in cancer cells. In a complementary approach, we performed depletion of NDPK-D by RNA interference. Both loss-of-function mutations and NDPK-D depletion promoted epithelial-mesenchymal transition and increased migratory and invasive potential. Immunocompromised mice developed more metastases when injected with cells expressing mutant NDPK-D as compared to wild-type. This metastatic reprogramming is a consequence of mitochondrial alterations, including fragmentation and loss of mitochondria, a metabolic switch from respiration to glycolysis, increased ROS generation, and further metabolic changes in mitochondria, all of which can trigger pro-metastatic protein expression and signaling cascades. In human cancer, NME4 expression is negatively associated with markers of epithelial-mesenchymal transition and tumor aggressiveness and a good prognosis factor for beneficial clinical outcome. Conclusions These data demonstrate NME4 as a novel metastasis suppressor gene, the first localizing to mitochondria, pointing to a role of mitochondria in metastatic dissemination.
Keywords
- Mitochondrial dynamics
- Invasion
- Metastasis
- Nucleoside diphosphate kinase
- NME4
- Metabolic reprogramming