Transcriptional control of autophagy–lysosome function drives pancreatic cancer metabolism

The MiT/TFE family of transcription factors is found to coordinate constitutive activation of autophagy and lysosome biogenesis to drive the metabolic programming and malignant growth of pancreatic cancer. Various cancers including pancreatic ductal adenocarcinoma (PDA) are known to depend on high levels of autophagy, the highly conserved self-degradative process required in normal cells for nutrient scavenging and quality control activities. Here Rushika Perera et al. describe a previously unknown link between cellular stress and autophagy leading to altered cell metabolism in pancreatic cancer. They show that aberrant expression and constitutive activation of the MiT/TFE family transcription factors mediates metabolic reprogramming through greatly enhanced autophagy–lysosomal function in human PDA specimens and cell lines. These findings identify lysosome regulation as a focus for nutrient utilization and energy homeostasis in cancer cells. Activation of cellular stress response pathways to maintain metabolic homeostasis is emerging as a critical growth and survival mechanism in many cancers1. The pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy2,3,4, a conserved self-degradative process5. However, the regulatory circuits that activate autophagy and reprogram PDA cell metabolism are unknown. Here we show that autophagy induction in PDA occurs as part of a broader transcriptional program that coordinates activation of lysosome biogenesis and function, and nutrient scavenging, mediated by the MiT/TFE family of transcription factors. In human PDA cells, the MiT/TFE proteins6—MITF, TFE3 and TFEB—are decoupled from regulatory mechanisms that control their cytoplasmic retention. Increased nuclear import in turn drives the expression of a coherent network of genes that induce high levels of lysosomal catabolic function essential for PDA growth. Unbiased global metabolite profiling reveals that MiT/TFE-dependent autophagy–lysosome activation is specifically required to maintain intracellular amino acid pools. These results identify the MiT/TFE proteins as master regulators of metabolic reprogramming in pancreatic cancer and demonstrate that transcriptional activation of clearance pathways converging on the lysosome is a novel hallmark of aggressive malignancy.