MYC 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 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.

Automated summary

Amplification of the proto-oncogene MYCN is a key molecular aberration in high-risk neuroblastoma, affecting the protein cargo of extracellular vesicles (EVs) secreted by tumour cells and influencing the Warburg effect, proliferation, and c-MYC expression in recipient cells. The cancer-promoting activity of EVs was linked to the glycolytic kinase pyruvate kinase M2 (PKM2) enriched in EVs secreted by MYC-expressing neuroblastoma cells. Glycolytic enzymes PKM2 and hexokinase II were detected in EVs circulating in neuroblastoma patients but not in non-cancer children, indicating potential spread of oncogenic signals via EVs from MYC-activated cancers.