MYC regulates metabolism through vesicular transfer of glycolytic kinases
Alexia Tsakaneli,
Victor Corasolla Carregari,
Martina Morini,
Alessandra Eva,
Giuliana Cangemi,
Olesya Chayka,
Evgeny Makarov,
Sandra Bibbò,
Emily Capone,
Gianluca Sala,
Vincenzo De Laurenzi,
Evon Poon,
Louis Chesler,
Luisa Pieroni,
Martin R. Larsen,
Giuseppe Palmisano,
Arturo Sala
Affiliations
Alexia Tsakaneli
Institute of Environment, Health and Societies, Department of Life Sciences, Brunel University London, UB8 3PH Uxbridge, UK
Victor Corasolla Carregari
GlycoProteomics Laboratory, Department of Parasitology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 1374 Sao Paulo, Brazil
Martina Morini
Laboratorio di Biologia Molecolare, IRCCS Istituto G. Gaslini, Genoa, Italy
Alessandra Eva
Laboratorio di Biologia Molecolare, IRCCS Istituto G. Gaslini, Genoa, Italy
Giuliana Cangemi
Laboratorio di Analisi, IRCCS Istituto G. Gaslini, Genoa, Italy
Olesya Chayka
Institute of Environment, Health and Societies, Department of Life Sciences, Brunel University London, UB8 3PH Uxbridge, UK
Evgeny Makarov
Institute of Environment, Health and Societies, Department of Life Sciences, Brunel University London, UB8 3PH Uxbridge, UK
Sandra Bibbò
Department of Innovative Technologies in Medicine and Dentistry, University of Chieti-Pescara, Center for Advanced Studies and Technology (CAST) Chieti, Italy
Emily Capone
Department of Innovative Technologies in Medicine and Dentistry, University of Chieti-Pescara, Center for Advanced Studies and Technology (CAST) Chieti, Italy
Gianluca Sala
Department of Innovative Technologies in Medicine and Dentistry, University of Chieti-Pescara, Center for Advanced Studies and Technology (CAST) Chieti, Italy
Vincenzo De Laurenzi
Department of Innovative Technologies in Medicine and Dentistry, University of Chieti-Pescara, Center for Advanced Studies and Technology (CAST) Chieti, Italy
Evon Poon
Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, London, UK
Louis Chesler
Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, London, UK
Luisa Pieroni
Department of Experimental Neuroscience, Proteomics and Metabonomics Unit, Fondazione Santa Lucia-IRCCS, Rome, Italy
Martin R. Larsen
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
Giuseppe Palmisano
GlycoProteomics Laboratory, Department of Parasitology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 1374 Sao Paulo, Brazil
Arturo Sala
Institute of Environment, Health and Societies, Department of Life Sciences, Brunel University London, UB8 3PH Uxbridge, UK
Amplification of the proto-oncogene MYCN is a key molecular aberration in high-risk neuroblastoma and predictive of poor outcome in this childhood malignancy. We investigated the role of MYCN in regulating the protein cargo of extracellular vesicles (EVs) secreted by tumour cells that can be internalized by recipient cells with functional consequences. Using a switchable MYCN system coupled to mass spectrometry analysis, we found that MYCN regulates distinct sets of proteins in the EVs secreted by neuroblastoma cells. EVs produced by MYCN-expressing cells or isolated from neuroblastoma patients induced the Warburg effect, proliferation and c-MYC expression in target cells. Mechanistically, we linked the cancer-promoting activity of EVs to the glycolytic kinase pyruvate kinase M2 (PKM2) that was enriched in EVs secreted by MYC-expressing neuroblastoma cells. Importantly, the glycolytic enzymes PKM2 and hexokinase II were detected in the EVs circulating in the bloodstream of neuroblastoma patients, but not in those of non-cancer children. We conclude that MYC-activated cancers might spread oncogenic signals to remote body locations through EVs.
