Fellow Focus: Roberto Zoncu
Malignant melanoma cells depend on the amino acid leucine, according to recent research by JCC fellow Roberto Zoncu published in the May 2011 issue of Cancer Cell. Zoncu and his coauthors found that melanoma cells with a mutation in the RAS/MEK signaling pathwaythe most common mutation found in the deadliest form of skin cancerdied when leucine was withheld.
When cells are starving, they repurpose some of their own old and damaged parts, breaking them down into their components and reusing the raw materials. This process, known as autophagy, is particularly relevant to cancer cells, which often grow in nutrient-limited conditions.
Autophagy is triggered when a specific pathway, the mTOR pathway, senses that nutrients are scarce. Zoncu and his coauthors discovered that leucine is a critical component. Without leucine, the melanoma cells did not recognize the nutrient shortage. But leucine is required for basic functions, so the cancer cells eventually died when they reached a metabolic crisis.
“My specific contribution to this work was to identify a cellular mechanism that prevents melanoma cells from triggering autophagy in response to leucine deprivation,” says Zoncu, who is a postdoc in David Sabatinis lab at the Whitehead Institute.
Normally, leucine activates mTORC1 by recruiting it to lysosomes and suppressing autophagy. When leucine is removed, mTORC1 detaches from lysosomes and allows autophagy to proceed. Using confocal microscopy, Zoncu found that, in the melanoma cells studied, the mTORC1 remained attached to lysosomes even without leucine, preventing autophagy and leading to cell death.
“The hope is that, eventually, the research could be useful in developing future melanoma treatments. These findings are exciting because they reveal a novel mechanism through which the RAS oncogene may drive tumor growth, namely, by forcing the localization and activation of mTORC1 to the lysosome,” says Zoncu. While forced localization of mTORC1 likely contributes to driving tumor growth, it also introduces a selective liability of melanoma cells that occurs upon deprivation of leucine, and which may be exploited for therapeutic purposes.