美国斯隆凯特林研究所Ming O. Li研究小组重编程肿瘤相关巨噬细胞来战胜癌细胞。2023年6月28日出版的《自然》杂志发表了这项成果。

研究人员表明，肿瘤相关的巨噬细胞（TAM）可以通过饮食或基因重新编程来竞争MYC过表达的癌细胞。在乳腺癌的小鼠模型中，MYC过表达导致mTORC1依赖的“赢家”癌细胞状态。低蛋白饮食抑制了癌细胞的mTORC1信号，并减少了肿瘤的生长，这意外地是由于转录因子TFEB和TFE3以及TAM的mTORC1激活。饮食中的细胞氨基酸通过GTP酶激活蛋白GATOR1和FLCN被Rag GTP酶感知，从而控制包括TFEB和TFE在内的Rag GTP酶效应器。在低蛋白饮食条件下，TAM中GATOR1的耗竭抑制了TFEB、TFE3和mTORC1的激活，导致肿瘤加速生长；相反，在正常蛋白饮食条件下，TAM中FLCN或Rag GTP酶的消耗激活了TFEB、TFE3和mTORC1，导致肿瘤减速生长。

此外，TAM和癌细胞中的mTORC1过度激活和它们的竞争能力都依赖于内溶酶体吞噬调节器PIKfyve。因此，TAM中非经典吞噬介导的Rag GTP酶非依赖性mTORC1信号控制了TAM和癌细胞之间的竞争，这定义了一个新的先天免疫肿瘤抑制途径，可作为癌症治疗的靶点。

据了解，在后生生物体中，细胞竞争作为一种质量控制机制，以消除不合适的细胞而有利于其更强大的邻居。这种机制有可能适应不良，促进了侵略性癌细胞的选择。肿瘤是新陈代谢活跃的，并由基质细胞填充，但环境因素如何影响癌细胞的竞争在很大程度上仍然是未知的。

附：英文原文

Title: Reprogramming tumour-associated macrophages to outcompete cancer cells

Author: Zhang, Xian, Li, Shun, Malik, Isha, Do, Mytrang H., Ji, Liangliang, Chou, Chun, Shi, Wei, Capistrano, Kristelle J., Zhang, Jing, Hsu, Ting-Wei, Nixon, Briana G., Xu, Ke, Wang, Xinxin, Ballabio, Andrea, Schmidt, Laura S., Linehan, W. Marston, Li, Ming O.

Issue&Volume: 2023-06-28

Abstract: In metazoan organisms, cell competition acts as a quality control mechanism to eliminate unfit cells in favour of their more robust neighbours1,2. This mechanism has the potential to be maladapted, promoting the selection of aggressive cancer cells3,4,5,6. Tumours are metabolically active and are populated by stroma cells7,8, but how environmental factors affect cancer cell competition remains largely unknown. Here we show that tumour-associated macrophages (TAMs) can be dietarily or genetically reprogrammed to outcompete MYC-overexpressing cancer cells. In a mouse model of breast cancer, MYC overexpression resulted in an mTORC1-dependent ‘winner’ cancer cell state. A low-protein diet inhibited mTORC1 signalling in cancer cells and reduced tumour growth, owing unexpectedly to activation of the transcription factors TFEB and TFE3 and mTORC1 in TAMs. Diet-derived cytosolic amino acids are sensed by Rag GTPases through the GTPase-activating proteins GATOR1 and FLCN to control Rag GTPase effectors including TFEB and TFE39,10,11,12,13,14. Depletion of GATOR1 in TAMs suppressed the activation of TFEB, TFE3 and mTORC1 under the low-protein diet condition, causing accelerated tumour growth; conversely, depletion of FLCN or Rag GTPases in TAMs activated TFEB, TFE3 and mTORC1 under the normal protein diet condition, causing decelerated tumour growth. Furthermore, mTORC1 hyperactivation in TAMs and cancer cells and their competitive fitness were dependent on the endolysosomal engulfment regulator PIKfyve. Thus, noncanonical engulfment-mediated Rag GTPase-independent mTORC1 signalling in TAMs controls competition between TAMs and cancer cells, which defines a novel innate immune tumour suppression pathway that could be targeted for cancer therapy.

DOI: 10.1038/s41586-023-06256-5

Source: https://www.nature.com/articles/s41586-023-06256-5