MYC regulates metabolism through vesicular transfer of glycolytic kinases

Abstract

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.

Glutamine addiction is targetable via altering splicing of nutrient sensors and epitranscriptome regulators

“…Despite strong mRNA and protein validation of the PKM isoform switching, metabolic tracing did not show any consistent effects on glucose metabolism; additionally oxidative phosphorylation was also unaltered (data not shown). However, PKM2 also phosphorylates non-metabolic substrates, for example stabilizing Bcl-2 (61) and influencing transcription via phosphorylation of histone 3, already demonstrated in neuroblastoma (62), and perturbation of these pathways may contribute to GSK3203591-mediated growth inhibition. Numerous other DEGs and DSGs identified by our transcriptomic analyses encode metabolic pathway proteins.…”

Sex-specific adipose tissue’s dynamic role in metabolic and inflammatory response following peripheral nerve injury

“… 71 The LC-MS analysis were performed as previously described. 10 , 38 , 72 The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE 73 partner repository with the dataset identifier PXD030391 and 10.6019/PXD030391.…”

Extracellular vesicles in neuroblastoma: role in progression, resistance to therapy and diagnostics

“…Cancer cells have known to mainly rely on aerobic glycolysis for sustained growth and metastasis, and specifically to adapt to new environment at secondary locations. In MYCN-amplified NBs, MYCN was found to transfer such aggressive, oncogenic phenotype to other non-MYCN amplified NB cells and surrounding stromal cells by regulating the host cell EV-protein cargo thereby promoting tumor progression ( 75 ).…”