Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors.
Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors.
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DOI：
10.1038/nm.4256
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发表时间：
2017-02
期刊：
影响因子：
82.9
通讯作者：
Vander Heiden MG
中科院分区：
文献类型：
--
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
通过巨胞饮作用清除蛋白质可以作为胰腺癌细胞的营养来源。我们提供了直接的证据，细胞外蛋白质是体内胰腺癌细胞的燃料来源。我们证明白蛋白衍生的肽和氨基酸在Kras驱动的胰腺导管腺癌小鼠模型的肿瘤中积累。此外，我们实现了一种装置，将大分子直接输送到肿瘤中，并观察胰腺肿瘤内癌细胞的蛋白质催化和巨胞饮作用。巨胞饮抑制剂的局部释放导致肿瘤组织中氨基酸水平的急剧降低，这表明细胞外蛋白的直接摄取和催化是向肿瘤中的胰腺癌细胞提供氨基酸所必需的。这些数据提供了白蛋白被肿瘤催化的证据，也提出了一种利用胰腺癌细胞吞噬细胞外蛋白的倾向来测试治疗方法的方法。
Protein scavenging by macropinocytosis can serve as a source of nutrients for pancreatic cancer cells. We provide direct evidence that extracellular protein is a fuel source for pancreatic cancer cells in vivo. We demonstrate that albumin-derived peptides and amino acids accumulate in tumors in a Kras-driven mouse model of pancreatic ductal adenocarcinoma. In addition, we implement a device to deliver large molecules directly into the tumor and observe protein catabolism and macropinocytosis by cancer cells within pancreatic tumors. Local release of a macropinocytosis inhibitor leads to a drastic reduction in amino acids levels in tumor tissue arguing that the direct uptake and catabolism of extracellular protein is necessary to provide amino acids to pancreatic cancer cells in tumors. These data provide evidence for albumin catabolism by tumors and also suggest a method for testing therapies that take advantage of the propensity of pancreatic cancer cells to scavenge extracellular protein.