Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein.
Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein.
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DOI：
10.1158/0008-5472.can-14-2211
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发表时间：
2015-02-01
期刊：
影响因子：
11.2
通讯作者：
Rabinowitz JD
中科院分区：
文献类型：
--
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
葡萄糖和氨基酸是支持细胞生长的关键营养素。氨基酸作为单体输入，但致癌KRAS诱导的另一种途径是通过巨噬细胞作用摄取细胞外蛋白质，随后溶酶体降解这些蛋白质作为氨基酸的来源。在这项研究中，我们检测了胰腺导管腺癌（PDAC）的代谢，PDAC是一种血管化不良的致死性kras驱动的恶性肿瘤。人体PDAC和良性邻近组织的代谢组学比较显示，肿瘤组织中葡萄糖、糖酵解中间体、磷酸肌酸和两种主要代谢底物氨基酸谷氨酰胺和丝氨酸含量较低。令人惊讶的是，PDAC积累了必需氨基酸。这种积累可能是由于细胞外蛋白质通过巨饮作用被降解，以满足谷氨酰胺的需求，这反过来又产生了大多数其他氨基酸的过量。与这一假设相一致的是，在原始人类PDAC标本中观察到活跃的巨红细胞增多。此外，在生理白蛋白存在的情况下，我们发现培养的小鼠PDAC细胞在缺乏单一必需氨基酸的培养基中无限生长，并且在缺乏游离氨基酸的情况下复制一次。在这些条件下生长的特点是谷氨酰胺消耗和必需氨基酸积累同时发生。总的来说，我们的研究结果表明，清除细胞外蛋白是PDAC中营养摄取的重要模式。
Glucose and amino acids are key nutrients supporting cell growth. Amino acids are imported as monomers, but an alternative route induced by oncogenic KRAS involves uptake of extracellular proteins via macropinocytosis and subsequent lysosomal degradation of these proteins as a source of amino acids. In this study, we examined the metabolism of pancreatic ductal adenocarcinoma (PDAC), a poorly vascularized lethal KRAS-driven malignancy. Metabolomic comparisons of human PDAC and benign adjacent tissue revealed that tumor tissue was low in glucose, upper glycolytic intermediates, creatine phosphate and the amino acids glutamine and serine, two major metabolic substrates. Surprisingly, PDAC accumulated essential amino acids. Such accumulation could arise from extracellular proteins being degraded through macropinocytosis in quantities necessary to meet glutamine requirements, which in turn produces excess of most other amino acids. Consistent with this hypothesis, active macropinocytosis is observed in primary human PDAC specimens. Moreover, in the presence of physiological albumin, we found that cultured murine PDAC cells grow indefinitely in media lacking single essential amino acids, and replicate once in the absence of free amino acids. Growth under these conditions was characterized by simultaneous glutamine depletion and essential amino acid accumulation. Overall, our findings argue that the scavenging of extracellular proteins is an important mode of nutrient uptake in PDAC.