At the junction of growth and starvation stands a signaling protein called mechanistic Target of Rapamycin Complex 1 (mTORC1). Inside the cell, mTORC1 regulates metabolism, growth, protein and organelle recycling (autophagy), proliferation, and survival. When something goes wrong in the pathway, various diseases such as cancer, obesity, and type 2 diabetes, can develop. An outstanding challenge is to understand how mTORC1 becomes activated in response to a wide variety of stimuli including nutrients, growth factors, and stressors, in normal and cancer states. Roberto Zoncu, PhD (Damon Runyon-Rachleff Innovator ’16-’17), and colleagues at the University of California, Berkeley, recently identified a lipid, cholesterol, as a novel nutrient input to mTORC1. They found that when cholesterol levels in organelles known as lysosomes are high, mTORC1 activity is switched on to initiate growth signals. Lysosomes are membrane-bound compartments where waste products are broken down and recycled. Lysosomes also serve as decision-making centers, where mTORC1 is switched on or off and therefore can dictate whether cells should grow or not. The way cholesterol, an essential building block for cellular growth and proliferation, activates mTORC1 appears to be highly specific and requires dedicated cholesterol-sensing proteins that reside at the lysosome. The study was published in the prestigious journal Science.

“This work advances our understanding of how mTORC1 integrates its many inputs, and could point the way to novel therapeutic avenues in cancer, particularly pancreatic cancers, where lysosome function and potentially mTORC1 activity are intimately associated with cancer growth,” says Zoncu.