Stress-adaptive mechanisms enable tumour cells to overcome metabolic constraints under nutrient and oxygen shortage. Aspartate is an endogenous metabolic limitation under hypoxic conditions, but the nature of the adaptive mechanisms that contribute to aspartate availability and hypoxic tumour growth are poorly understood. Here we identify GOT2-catalysed mitochondrial aspartate synthesis as an essential metabolic dependency for the proliferation of pancreatic tumour cells under hypoxic culture conditions. In contrast, GOT2-catalysed aspartate synthesis is dispensable for pancreatic tumour formation in vivo. The dependence of pancreatic tumour cells on aspartate synthesis is bypassed in part by a hypoxia-induced potentiation of extracellular protein scavenging via macropinocytosis. This effect is mutant KRAS dependent, and is mediated by hypoxia-inducible factor 1 (HIF1A) and its canonical target carbonic anhydrase-9 (CA9). Our findings reveal high plasticity of aspartate metabolism and define an adaptive regulatory role for macropinocytosis by which mutant KRAS tumours can overcome nutrient deprivation under hypoxic conditions.

应激适应机制使肿瘤细胞能够克服营养和氧气短缺下的代谢限制。天冬氨酸是缺氧条件下的内源性代谢限制，但对天冬氨酸可用性和缺氧肿瘤生长的适应性机制的性质知之甚少。在这里，我们将 GOT2 催化的线粒体天冬氨酸合成确定为胰腺肿瘤细胞在缺氧培养条件下增殖的基本代谢依赖性。相比之下，GOT2 催化的天冬氨酸合成对于体内胰腺肿瘤的形成是可有可无的。胰腺肿瘤细胞对天冬氨酸合成的依赖性被巨胞饮作用引起的细胞外蛋白质清除增强的缺氧诱导部分绕过。这种作用是突变的KRAS依赖性，并由缺氧诱导因子 1 (HIF1A) 及其典型靶标碳酸酐酶 9 (CA9) 介导。我们的研究结果揭示了天冬氨酸代谢的高可塑性，并定义了巨胞饮作用的适应性调节作用，突变的KRAS 肿瘤可以通过这种作用克服缺氧条件下的营养剥夺。