包括胰腺导管腺癌(PDA)在内的各种不同癌症已知取决于高水平的自噬过程，它是正常细胞中营养清除和质量控制活动所需的高度保守的自行降解过程。在这项研究中，Rushika Perera等人描述了细胞压力和自噬过程之间在胰腺癌中导致细胞代谢被改变的一个以前人们不知道的联系。他们发现，MiT/TFE家族转录因子的异常表达和组成性激发，通过人类PDA标本和细胞系中大大增强的自噬-溶酶体功能介导代谢重新编程。这些发现说明，溶酶体调控是癌细胞中营养利用和能量平衡的一个焦点。

原文摘要:

Activation of cellular stress response pathways to maintain metabolic homeostasis is emerging as a critical growth and survival mechanism in many cancers. The pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy, a conserved self-degradative process. 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 proteins—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.