MYCN Regulates Metabolism Through Vesicular Transfer of Glycolytic Kinases

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 extracellular vesicles to the glycolytic kinase pyruvate kinase M2 (PKM2) that was enriched in EVs secreted by MYCN expressing neuroblastoma cells. Importantly, the glycolytic enzymes PKM2 and Hexokinase II were detected in the EVs circulating in the blood stream 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 extracellular vesicles.

Keywords: neuroblastoma, MYC, Warburg effect, Extracellular Vesicles, Mass Spectrometry

Suggested Citation: Suggested Citation

Tsakaneli, Alexia and Corasolla Carregari, Victor and Morini, Martina and Eva, Alessandra and Cangemi, Giuliana and Chayka, Olesya and Makarov, Evgeni and Poon, Evon and Chesler, Louis and Pieroni, Luisa and Larsen, Martin and Palmisano, Giuseppe and Sala, Arturo, MYCN Regulates Metabolism Through Vesicular Transfer of Glycolytic Kinases. Available at SSRN: https://ssrn.com/abstract=3575127 or http://dx.doi.org/10.2139/ssrn.3575127

This version of the paper has not been formally peer reviewed.