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 Atg5 (atg5-KO) extends the survival of KRASG12V-driven tumor-bearing mice by 38%. atg5-KO tumors spread more slowly during late tumorigenesis, despite a faster onset. atg5-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 de novo asparagine synthesis. Inhibition of either autophagy or ASNS reduced KRASG12V-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.

基底自噬缺陷限制了细胞内成分循环对营养物质的供应。尽管我们对巨自噬/自噬在生存作用上的理解已较为深入，但自噬功能受损导致的营养剥夺如何影响由癌基因KRAS驱动的肿瘤进展，这一机制尚不清楚。在本研究中，我们证实条件性敲除自噬基因Atg5（atg5-KO）通过延长KRASG12V驱动肿瘤小鼠的生存期38%，减缓了晚期肿瘤发生过程中的肿瘤扩散，尽管肿瘤的发生速度加快。atg5-KO肿瘤细胞表现出线粒体功能的下降和线粒体断裂的增加。代谢物分析表明，尽管ASNS（天冬酰胺合成酶）的补偿性过表达（天冬酰胺合成酶是合成天冬酰胺的关键酶），但非必需氨基酸天冬酰胺的缺乏依然存在。抑制自噬或ASNS可降低KRASG12V驱动肿瘤细胞的增殖、迁移和侵袭，而这种影响可通过天冬酰胺补充或MFF（线粒体分裂因子）的敲低得到逆转。最终，这些观察结果在人类癌症来源的数据中得到反映，将ASNS的高表达与多种癌症的较差临床预后联系起来。综上所述，我们的数据记录了自噬和ASNS在广泛且特异性地调节天冬酰胺稳态中的作用，突出了自噬在抑制低天冬酰胺和过度线粒体断裂代谢障碍方面的先前未被认识的作用，这些障碍允许恶性KRAS驱动肿瘤的进展。