Glutamine Deprivation Regulates the Origin and Function of Cancer Cell Exosomes
Glutamine Deprivation Regulates the Origin and Function of Cancer Cell Exosomes
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DOI：
10.1101/859447
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发表时间：
2019-12
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通讯作者：
Shih‐Jung Fan;Benjamin Kroeger;Pauline P Marie;E. Bridges;John D. Mason;K. McCormick;C. Zois;H. Sheldon;N. K. Alham;Errin Johnson;M. Ellis;M. I. Stefana;C. Mendes;S. Wainwright;C. Cunningham;F. Hamdy;J. Morris;A. Harris;Clive Wilson;D. Goberdhan
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作者：
Shih‐Jung Fan;Benjamin Kroeger;Pauline P Marie;E. Bridges;John D. Mason;K. McCormick;C. Zois;H. Sheldon;N. K. Alham;Errin Johnson;M. Ellis;M. I. Stefana;C. Mendes;S. Wainwright;C. Cunningham;F. Hamdy;J. Morris;A. Harris;Clive Wilson;D. Goberdhan
外泌体是一种分泌的细胞外囊泡，携带多种物质，可调节受体细胞的行为。它们被认为来源于在晚期内体多泡体（MVB）中形成的管腔内囊泡。本文描述了一种从苍蝇到人类都保守的替代外泌体形成机制，外泌体携带独特的货物，包括Rab 11阳性回收内体MVB中产生的GTPase Rab 11。这些外泌体从癌细胞的释放通过减少Akt/雷帕霉素的机械靶标（mTORC 1）信号传导或消耗关键代谢底物谷氨酰胺来增加，谷氨酰胺通过再循环内体转移膜通量。所产生的囊泡促进肿瘤细胞增殖和周转，并在体内异种移植小鼠模型中调节血管网络。它们的促生长活性，这也是在体外观察到的，是Rab 11 a依赖性的，涉及ERK-MAPK信号传导，并被抗体抑制双调蛋白，EGFR配体集中在这些囊泡。因此，谷氨酰胺耗竭或mTORC 1抑制刺激释放Rab 11 a-外泌体与促肿瘤功能，我们建议促进应激诱导的肿瘤适应。
Exosomes are secreted extracellular vesicles (EVs) carrying diverse cargos, which can modulate recipient cell behaviour. They are thought to derive from intraluminal vesicles formed in late endosomal multivesicular bodies (MVBs). An alternate exosome formation mechanism, which is conserved from fly to human, is described here, with exosomes carrying unique cargos, including the GTPase Rab11, generated in Rab11-positive recycling endosomal MVBs. Release of these exosomes from cancer cells is increased by reducing Akt/mechanistic Target of Rapamycin (mTORC1) signalling or depleting the key metabolic substrate glutamine, which diverts membrane flux through recycling endosomes. The resulting vesicles promote tumour cell proliferation and turnover, and modulate blood vessel networks in xenograft mouse models in vivo. Their growth-promoting activity, which is also observed in vitro, is Rab11a-dependent, involves ERK-MAPK-signalling and is inhibited by antibodies against Amphiregulin, an EGFR ligand concentrated on these vesicles. Therefore, glutamine depletion or mTORC1 inhibition stimulates release of Rab11a-exosomes with pro-tumorigenic functions, which we propose promote stress-induced tumour adaptation.