Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer.
Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer.
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DOI：
10.1038/nature22341
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发表时间：
2017-06-22
期刊：
影响因子：
64.8
通讯作者：
Kalluri R
中科院分区：
文献类型：
--
作者：
Kamerkar S;LeBleu VS;Sugimoto H;Yang S;Ruivo CF;Melo SA;Lee JJ;Kalluri R
GTPase KRAS的突变形式是胰腺癌的关键驱动因素，但仍是一个具有挑战性的治疗靶点。外体是由所有细胞产生的细胞外小泡，自然存在于血液中。在这里，我们证明，与脂质体相比，外切体在循环中的滞留能力增强是由于CD47介导的保护外切体免受单核细胞和巨噬细胞吞噬的作用。来自正常成纤维细胞样间充质细胞的Exosome被设计成携带针对致癌KrasG12D(IExosome)的siRNA或shRNA，iExosome是胰腺癌中常见的突变。与脂质体相比，iExosome靶向致癌的Kras具有依赖于CD47的增强疗效，并受到巨噬细胞吞噬的促进。IExosome治疗抑制了多种胰腺癌小鼠模型的癌症，并显著提高了它们的总存活率。我们的结果为使用iExosome直接和特异性靶向肿瘤中的致癌Kras提供了一种新的方法。
The mutant form of the GTPase KRAS is a key driver of pancreatic cancer but remains a challenging therapeutic target. Exosomes, extracellular vesicles generated by all cells, are naturally present in the blood. Here we demonstrate that enhanced retention of exosomes in circulation, compared to liposomes, is due to CD47 mediated protection of exosomes from phagocytosis by monocytes and macrophages. Exosomes derived from normal fibroblast-like mesenchymal cells were engineered to carry siRNA or shRNA specific to oncogenic KRASG12D (iExosomes), a common mutation in pancreatic cancer. Compared to liposomes, iExosomes target oncogenic Kras with an enhanced efficacy that is dependent on CD47, and is facilitated by macropinocytosis. iExosomes treatment suppressed cancer in multiple mouse models of pancreatic cancer and significantly increased their overall survival. Our results inform on a novel approach for direct and specific targeting of oncogenic Kras in tumors using iExosomes.
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