Cell-programmed nutrient partitioning in the tumour microenvironment.
Cell-programmed nutrient partitioning in the tumour microenvironment.
复制标题
DOI：
10.1038/s41586-021-03442-1
复制
发表时间：
2021-05
期刊：
影响因子：
64.8
通讯作者：
Rathmell WK
中科院分区：
文献类型：
--
作者：
Reinfeld BI;Madden MZ;Wolf MM;Chytil A;Bader JE;Patterson AR;Sugiura A;Cohen AS;Ali A;Do BT;Muir A;Lewis CA;Hongo RA;Young KL;Brown RE;Todd VM;Huffstater T;Abraham A;O'Neil RT;Wilson MH;Xin F;Tantawy MN;Merryman WD;Johnson RW;Williams CS;Mason EF;Mason FM;Beckermann KE;Vander Heiden MG;Manning HC;Rathmell JC;Rathmell WK
癌细胞的特征是通过Warburg代谢消耗葡萄糖，这一过程形成了正电子发射断层扫描（PET）肿瘤成像的基础。肿瘤浸润性免疫细胞也依赖于葡萄糖，肿瘤微环境（Tumor microenvironment， TME）中免疫细胞代谢受损导致肿瘤免疫逃逸。然而，在TME中，免疫细胞代谢失调是由于细胞固有程序还是由于与癌细胞竞争限制营养物质，目前仍不确定。在这里，我们使用PET示踪剂来测量TME中特定细胞亚群对葡萄糖和谷氨酰胺的获取和摄取。令人惊讶的是，在一系列癌症模型中，骨髓细胞吸收肿瘤内葡萄糖的能力最强，其次是T细胞和癌细胞。相比之下，癌细胞表现出最高的谷氨酰胺摄取。这种独特的营养分配是通过mTORC1信号和葡萄糖和谷氨酰胺相关基因表达在细胞内部编程的。抑制谷氨酰胺摄取增强了肿瘤驻留细胞类型的葡萄糖摄取，表明谷氨酰胺代谢抑制葡萄糖摄取，而葡萄糖在TME中不受限制。因此，细胞内在程序分别驱动免疫细胞和癌细胞优先获得葡萄糖和谷氨酰胺。这些营养物质的细胞选择性分配可能被用于开发治疗和成像策略，以增强或监测TME中特定细胞群的代谢程序和活动。
Cancer cells characteristically consume glucose through Warburg metabolism, a process forming the basis of tumor imaging by positron emission tomography (PET). Tumor infiltrating immune cells also rely on glucose, and impaired immune cell metabolism in the tumor microenvironment (TME) contributes to tumor immunological evasion. It remains uncertain, however, if immune cell metabolism is dysregulated in the TME by cell intrinsic programs or by competition with cancer cells for limiting nutrients. Here we used PET tracers to measure access and uptake of glucose and glutamine by specific cell subsets in the TME. Surprisingly, myeloid cells had the greatest capacity to uptake intra-tumoral glucose, followed by T cells and cancer cells across a range of cancer models. Cancer cells, in contrast, demonstrated the highest glutamine uptake. This distinct nutrient partitioning was cell intrinsically programmed through mTORC1 signaling and glucose and glutamine-related gene expression. Inhibiting glutamine uptake enhanced glucose uptake across tumor resident cell types, demonstrating that glutamine metabolism suppresses glucose uptake without glucose being limiting in the TME. Thus, cell intrinsic programs drive the preferential immune and cancer cell acquisition of glucose and glutamine, respectively. Cell selective partitioning of these nutrients may be exploited to develop therapies and imaging strategies to enhance or monitor the metabolic programs and activities of specific cell populations in the TME.
登录
查看更多内容
影响因子：
29
作者：
Cascone T;McKenzie JA;Mbofung RM;Punt S;Wang Z;Xu C;Williams LJ;Wang Z;Bristow CA;Carugo A;Peoples MD;Li L;Karpinets T;Huang L;Malu S;Creasy C;Leahey SE;Chen J;Chen Y;Pelicano H;Bernatchez C;Gopal YNV;Heffernan TP;Hu J;Wang J;Amaria RN;Garraway LA;Huang P;Yang P;Wistuba II;Woodman SE;Roszik J;Davis RE;Davies MA;Heymach JV;Hwu P;Peng W
通讯作者：
Peng W
影响因子：
11.2
作者：
Hesketh, Richard L.;Wang, Jiazheng;Brindle, Kevin M.
通讯作者：
Brindle, Kevin M.
影响因子：
64.5
作者：
Ho PC;Bihuniak JD;Macintyre AN;Staron M;Liu X;Amezquita R;Tsui YC;Cui G;Micevic G;Perales JC;Kleinstein SH;Abel ED;Insogna KL;Feske S;Locasale JW;Bosenberg MW;Rathmell JC;Kaech SM
通讯作者：
Kaech SM
影响因子：
10.1
作者：
Cortese, Nina;Capretti, Giovanni;Marchesi, Federica
通讯作者：
Marchesi, Federica
影响因子：
11.2
作者：
Jeong, Hoibin;Kim, Sehui;Ahn, G-One
通讯作者：
Ahn, G-One