Human cancers with activating RAS mutations are typically highly aggressive and treatment-refractory, yet RAS mutation itself is insufficient for tumorigenesis, due in part to profound metabolic stress induced by RAS activation. Here we show that loss of REDD1, a stress-induced metabolic regulator, is sufficient to reprogram lipid metabolism and drive progression of RAS mutant cancers. Redd1 deletion in genetically engineered mouse models (GEMMs) of KRAS-dependent pancreatic and lung adenocarcinomas converts preneoplastic lesions into invasive and metastatic carcinomas. Metabolic profiling reveals that REDD1-deficient/RAS mutant cells exhibit enhanced uptake of lysophospholipids and lipid storage, coupled to augmented fatty acid oxidation that sustains both ATP levels and ROS-detoxifying NADPH. Mechanistically, REDD1 loss triggers HIF-dependent activation of a lipid storage pathway involving PPARγ and the prometastatic factor CD36. Correspondingly, decreased REDD1 expression and a signature of REDD1 loss predict poor outcomes selectively in RAS mutant but not RAS wild-type human lung and pancreas carcinomas. Collectively, our findings reveal the REDD1-mediated stress response as a novel tumor suppressor whose loss defines a RAS mutant tumor subset characterized by reprogramming of lipid metabolism, invasive and metastatic progression, and poor prognosis. This work thus provides new mechanistic and clinically relevant insights into the phenotypic heterogeneity and metabolic rewiring that underlies these common cancers.

中文翻译：

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REDD1丢失会重新编程脂质代谢，以驱动RAS突变肿瘤的进展。

具有激活的RAS突变的人类癌症通常具有很高的侵袭性和治疗难治性，但是RAS突变本身不足以用于肿瘤发生，部分原因是RAS激活引起的强烈的代谢应激。在这里，我们表明，REDD1（一种应力诱导的代谢调节剂）的丢失足以重新编程脂质代谢并驱动RAS突变癌症的进展。在KRAS依赖性胰腺癌和肺腺癌的基因工程小鼠模型（GEMM）中，Redd1缺失将肿瘤前病变转变为浸润性和转移性癌。代谢谱分析显示REDD1缺陷/ RAS突变细胞表现出更高的溶血磷脂摄取和脂质储存能力，与增强的脂肪酸氧化相结合，从而维持ATP水平和ROS解毒NADPH。从机理上讲，REDD1丢失会触发HIF依赖的涉及PPARγ和前转移因子CD36的脂质存储途径的激活。相应地，降低的REDD1表达和REDD1丢失的特征预示着RAS突变体选择性选择性不良，而RAS野生型人肺癌和胰腺癌则没有选择性。总的来说，我们的发现揭示了REDD1介导的应激反应是一种新型的肿瘤抑制因子，其丢失定义了RAS。突变的肿瘤亚群，其特征在于脂质代谢的重新编程，侵袭性和转移性进展以及预后不良。因此，这项工作为这些常见癌症的潜在表型异质性和代谢重新布线提供了新的机制和与临床相关的见解。