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包括胰腺導(dǎo)管腺癌(PDA)在內(nèi)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(xì)胞中營養(yǎng)清除和質(zhì)量控制活動(dòng)所需的高度保守的自行降解過程。在這項(xiàng)研究中，Rushika Perera等人描述了細(xì)胞壓力和自噬過程之間在胰腺癌中導(dǎo)致細(xì)胞代謝被改變的一個(gè)以前人們不知道的聯(lián)系。他們發(fā)現(xiàn)，MiT/TFE家族轉(zhuǎn)錄因子的異常表達(dá)和組成性激發(fā)，通過人類PDA標(biāo)本和細(xì)胞系中大大增強(qiáng)的自噬-溶酶體功能介導(dǎo)代謝重新編程。這些發(fā)現(xiàn)說明，溶酶體調(diào)控是癌細(xì)胞中營養(yǎng)利用和能量平衡的一個(gè)焦點(diǎn)。

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.