Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia.
Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia.
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DOI：
10.1038/s42255-022-00583-z
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发表时间：
2022-06
影响因子：
20.8
通讯作者：
Birsoy, Kivanc
中科院分区：
文献类型：
--
作者：
Garcia-Bermudez, Javier;Badgley, Michael A.;Prasad, Sheela;Baudrier, Lou;Liu, Yuyang;La, Konnor;Soula, Mariluz;Williams, Robert T.;Yamaguchi, Norihiro;Hwang, Rosa F.;Taylor, Laura J.;de Stanchina, Elisa;Rostandy, Bety;Alwaseem, Hanan;Molina, Henrik;Bar-Sagi, Dafna;Birsoy, Kivanc
压力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。天冬氨酸在缺氧条件下是一种内源性代谢限制，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，我们确定GOT 2催化的线粒体天冬氨酸合成作为一个重要的代谢依赖性的胰腺肿瘤细胞在缺氧培养条件下的增殖。相比之下，GOT 2催化的天冬氨酸合成对于体内胰腺肿瘤的形成是不利的。胰腺肿瘤细胞对天冬氨酸合成的依赖性部分被缺氧诱导的通过巨胞饮作用清除细胞外蛋白的增强所绕过。这种效应是突变型KRAS依赖性的，并且由缺氧诱导因子1（HIF 1A）及其典型靶点碳酸酐酶-9（CA 9）介导。我们的研究结果揭示了天冬氨酸代谢的高可塑性，并定义了巨胞饮的适应性调节作用，突变型KRAS肿瘤可以克服缺氧条件下的营养剥夺。
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.
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影响因子：
82.9
作者：
Davidson SM;Jonas O;Keibler MA;Hou HW;Luengo A;Mayers JR;Wyckoff J;Del Rosario AM;Whitman M;Chin CR;Condon KJ;Lammers A;Kellersberger KA;Stall BK;Stephanopoulos G;Bar-Sagi D;Han J;Rabinowitz JD;Cima MJ;Langer R;Vander Heiden MG
通讯作者：
Vander Heiden MG
影响因子：
29
作者：
Ducker GS;Chen L;Morscher RJ;Ghergurovich JM;Esposito M;Teng X;Kang Y;Rabinowitz JD
通讯作者：
Rabinowitz JD
影响因子：
11.2
作者：
Hwang, Rosa F.;Moore, Todd;Logsdon, Craig D.
通讯作者：
Logsdon, Craig D.
DOI：
10.1073/pnas.1307237110
发表时间：
2013-05-28
影响因子：
11.1
作者：
Kamphorst, Jurre J.;Cross, Justin R.;Rabinowitz, Joshua D.
通讯作者：
Rabinowitz, Joshua D.
影响因子：
11.2
作者：
Kamphorst JJ;Nofal M;Commisso C;Hackett SR;Lu W;Grabocka E;Vander Heiden MG;Miller G;Drebin JA;Bar-Sagi D;Thompson CB;Rabinowitz JD
通讯作者：
Rabinowitz JD