Myc influences glutamine metabolism to induce autophagy in tumorigenesis

Drosophila melanogaster is a valuable model for studying various aspects of human cancer, including proliferative capacity, invasiveness and metabolic adaptation typical of tumour cells to support cell growth. One of the major players in this process is Myc, which can promote tumorigenesis by triggering a metabolic reprogramming that allows cells to produce macromolecules, by modulating glycolytic flux, glutaminolysis, lipidogenesis, and autophagy. The process by which hyperproliferative cells undergo metabolic reprogramming to sustain growth can be recapitulated in the epithelial cells from Drosophila imaginal discs, where different levels of Myc induce cell competition. This process is a mechanism for selection of cells expressing higher level of Myc that acquire a super-competitor condition, with the ability to non-autonomously kill the neighbouring slow-growing cells. The direct connection between Myc, glutamine metabolism and autophagy and their role in competitive events between cancerous cells and wild type cells have not been clearly explained; therefore, the main purpose of this project is to determine a plausible link between Myc and autophagy, by examining the dependency of Myc-induced autophagy on glutaminase and major regulators of autophagy, such as TOR, Atg1, Atg5 and ammonia, a by-product of glutamine catabolism, by dissecting these mechanisms both in normal epithelial clones and hyperproliferating RasV12 -expressing cells. Our results show that Myc promotes the transcription of glutamine-related genes and the production of ammonia, and that glutaminase is necessary for Myc-induced autophagy in epithelial cells of clones of the wing imaginal discs, with a mechanism independent from TOR and Atg1. Conversely, the effect of Myc on autophagy induction is mediated by Atg5. We then investigated the contribute of Myc in autophagy in RasV12-transformed cells, that upregulate Myc to sustain growth and hyperproliferation. Intriguingly, our data report that autophagy is increased non-autonomously in neighbouring wild type cells, and that this non-autonomous RasV12-driven autophagic flux depends on Myc activity. Moreover, downregulation of glutaminase in RasV12-expressing cells significantly reduces non-autonomous autophagy. Collectively, our results give new insights on how glutamine metabolism can contribute to Myc-induced autophagy and how this enhances cancerous cell fitness.