Autophagic reliance promotes metabolic reprogramming in oncogenic KRAS-driven tumorigenesis

Defects in basal autophagy limit the nutrient supply from recycling of intracellular constituents. Despite our understanding of the prosurvival role of macroautophagy/autophagy, how nutrient deprivation, caused by compromised autophagy, affects oncogenic KRAS-driven tumor progression is poorly understood. Here, we demonstrate that conditional impairment of the autophagy gene <i>Atg5</i> (<i>atg5-</i>KO) extends the survival of KRAS^G12V-driven tumor-bearing mice by 38%. <i>atg5-</i>KO tumors spread more slowly during late tumorigenesis, despite a faster onset. <i>atg5-</i>KO tumor cells displayed reduced mitochondrial function and increased mitochondrial fragmentation. Metabolite profiles indicated a deficiency in the nonessential amino acid asparagine despite a compensatory overexpression of ASNS (asparagine synthetase), key enzyme for <i>de novo</i> asparagine synthesis. Inhibition of either autophagy or ASNS reduced KRAS^G12V-driven tumor cell proliferation, migration, and invasion, which was rescued by asparagine supplementation or knockdown of MFF (mitochondrial fission factor). Finally, these observations were reflected in human cancer-derived data, linking ASNS overexpression with poor clinical outcome in multiple cancers. Together, our data document a widespread yet specific asparagine homeostasis control by autophagy and ASNS, highlighting the previously unrecognized role of autophagy in suppressing the metabolic barriers of low asparagine and excessive mitochondrial fragmentation to permit malignant KRAS-driven tumor progression.

基础自噬（basal autophagy）的缺陷会限制细胞内组分回收所提供的营养供给。尽管我们对巨自噬/自噬（macroautophagy/autophagy）的促存活作用已有一定认知，但自噬功能受损引发的营养匮乏，如何影响致癌KRAS驱动的肿瘤进展，目前仍尚不明确。本研究证实，自噬基因Atg5的条件性敲除（atg5-KO）可使携带KRAS^G12V驱动肿瘤的小鼠生存期延长38%。尽管atg5-KO肿瘤的发生速度更快，但在肿瘤发生后期，其扩散速度更为缓慢。atg5-KO肿瘤细胞表现出线粒体功能降低、线粒体碎片化程度升高。代谢组谱分析显示，尽管天冬酰胺合成酶（ASNS, asparagine synthetase）——从头（de novo）合成天冬酰胺的关键酶——出现代偿性过表达，但非必需氨基酸天冬酰胺仍存在缺乏。抑制自噬或ASNS均可降低KRAS^G12V驱动的肿瘤细胞增殖、迁移与侵袭能力，该效应可通过补充天冬酰胺或敲低线粒体分裂因子（MFF, mitochondrial fission factor）得以逆转。最后，上述研究结果在人类癌症来源的数据中得到验证，即ASNS过表达与多种癌症的不良临床结局显著相关。综上，本研究揭示了自噬与ASNS介导的、广泛存在且具有特异性的天冬酰胺稳态调控机制，并阐明了此前未被认知的自噬功能：通过抑制低天冬酰胺代谢障碍与过度线粒体碎片化，从而支持KRAS恶性驱动的肿瘤进展。