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包括胰腺導管腺癌(PDA)在內的各種不同癌癥已知取決于高水平的自噬過程，它是正常細胞中營養清除和質量控制活動所需的高度保守的自行降解過程。在這項研究中，Rushika Perera等人描述了細胞壓力和自噬過程之間在胰腺癌中導致細胞代謝被改變的一個以前人們不知道的聯系。他們發現，MiT/TFE家族轉錄因子的異常表達和組成性激發，通過人類PDA標本和細胞系中大大增強的自噬-溶酶體功能介導代謝重新編程。這些發現說明，溶酶體調控是癌細胞中營養利用和能量平衡的一個焦點。

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.