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Cell-programmed nutrient partitioning in the tumour microenvironment
Nature ( IF 42.778 ) Pub Date : 2021-04-07 , DOI: 10.1038/s41586-021-03442-1
Bradley I. Reinfeld, Matthew Z. Madden, Melissa M. Wolf, Anna Chytil, Jackie E. Bader, Andrew R. Patterson, Ayaka Sugiura, Allison S. Cohen, Ahmed Ali, Brian T. Do, Alexander Muir, Caroline A. Lewis, Rachel A. Hongo, Kirsten L. Young, Rachel E. Brown, Vera M. Todd, Tessa Huffstater, Abin Abraham, Richard T. O’Neil, Matthew H. Wilson, Fuxue Xin, M. Noor Tantawy, W. David Merryman, Rachelle W. Johnson, Christopher S. Williams, Emily F. Mason, Frank M. Mason, Katherine E. Beckermann, Matthew G. Vander Heiden, H. Charles Manning, Jeffrey C. Rathmell, W. Kimryn Rathmell

Cancer cells characteristically consume glucose through Warburg metabolism1, a process that forms the basis of tumour imaging by positron emission tomography (PET). Tumour-infiltrating immune cells also rely on glucose, and impaired immune cell metabolism in the tumour microenvironment (TME) contributes to immune evasion by tumour cells2,3,4. However, whether the metabolism of immune cells is dysregulated in the TME by cell-intrinsic programs or by competition with cancer cells for limited nutrients remains unclear. Here we used PET tracers to measure the access to and uptake of glucose and glutamine by specific cell subsets in the TME. Notably, myeloid cells had the greatest capacity to take up intratumoral glucose, followed by T cells and cancer cells, across a range of cancer models. By contrast, cancer cells showed the highest uptake of glutamine. This distinct nutrient partitioning was programmed in a cell-intrinsic manner through mTORC1 signalling and the expression of genes related to the metabolism of glucose and glutamine. Inhibiting glutamine uptake enhanced glucose uptake across tumour-resident cell types, showing that glutamine metabolism suppresses glucose uptake without glucose being a limiting factor in the TME. Thus, cell-intrinsic programs drive the preferential acquisition of glucose and glutamine by immune and cancer cells, respectively. Cell-selective partitioning of these nutrients could be exploited to develop therapies and imaging strategies to enhance or monitor the metabolic programs and activities of specific cell populations in the TME.



中文翻译:

肿瘤微环境中细胞程序化的营养物分配

癌细胞通常通过Warburg代谢1消耗葡萄糖,Warburg代谢是通过正电子发射断层扫描(PET)形成肿瘤成像的基础的过程。肿瘤浸润性免疫细胞还依赖于葡萄糖,并且肿瘤微环境(TME)中免疫细胞代谢受损导致肿瘤细胞逃避免疫2,3,4。然而,尚不清楚在TME中免疫细胞的代谢是通过细胞内源性程序失调还是通过与癌细胞争夺有限的营养素而失调的。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访问和摄取。值得注意的是,在一系列癌症模型中,髓样细胞具有最大的摄取肿瘤内葡萄糖的能力,其次是T细胞和癌细胞。相反,癌细胞显示出最高的谷氨酰胺吸收。通过mTORC1信号传导以及与葡萄糖和谷氨酰胺代谢相关的基因表达,以细胞内在的方式对这种独特的营养分配进行了编程。抑制谷氨酰胺的摄取增强了跨肿瘤驻留细胞类型的葡萄糖摄取,表明谷氨酰胺代谢抑制了葡萄糖的摄取,而葡萄糖不是TME中的限制因素。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用于开发疗法和成像策略,以增强或监测TME中特定细胞群的代谢程序和活性。

更新日期:2021-04-08
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