MYC regulates metabolism through vesicular transfer of glycolytic kinases.

Alexia Tsakaneli,Victor Corasolla Carregari,Evgeny Makarov,Martina Morini,Giuseppe Palmisano,Sandra Bibbò,Arturo Sala,Emily Capone,Alessandra Eva,Olesya Chayka,Gianluca Sala,Vincenzo De Laurenzi,Evon Poon,Giuliana Cangemi,Louis Chesler,Martin R Larsen,Luisa Pieroni

doi:10.1098/rsob.210276

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.

Highlights

Neuroblastoma is a childhood malignancy originating from the peripheral nervous system that is still a leading cause of oncological death
Extracellular vesicles secreted by neuroblastoma cells with activated MYCN are enriched in oncogenic glycolytic enzymes
Pathway analysis suggests that glycolytic enzymes, ribosomal and extracellular matrix (ECM) interaction proteins were mostly enriched in the extracellular vesicles (EVs) secreted by the MYCN-positive cells

Summary

Introduction

Neuroblastoma is a childhood malignancy originating from the peripheral nervous system that is still a leading cause of oncological death. It was shown that cancer cells expressing MYC proteins modify the tumour microenvironment via the activation or inactivation of growth factors, cytokines and immune checkpoint regulators [4,5,6]. The hypothesis that MYC expression could induce non-cell autonomous effects is supported by evidence of heterogeneous (focal) amplification of MYCN in neuroblastoma tumours. We hypothesized that MYCN could promote neuroblastoma growth by regulating the secretion or content of extracellular vesicles (EVs) which would modify the metabolic activity of recipient cells. While the pro-tumourigenic or pro-metastatic role of EVs has been highlighted in different types of adult cancers [10,11,12,13,14,15,16] it is not known whether they play a role in the context of MYCN-amplified neuroblastoma

Methods

Results

Conclusion