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在体内，不同的细胞之间存在互相竞争、适者生存的机制，这种机制既可清除不健康的细胞，也可促进癌细胞的生长。尤其，癌细胞营养代谢活跃，必然受到饮食因素的影响。既往研究发现，高蛋白质饮食可能促进淋巴瘤、抑制肝癌和食管癌，低蛋白质饮食可能促进肝癌和食管癌、抑制乳腺癌，因此饮食蛋白质过高或过低都可能影响癌细胞竞争“上岗”。那么，饮食因素究竟如何影响癌细胞竞争“上岗”呢？正常蛋白质饮食能否抑制乳腺癌？ 2023年6月28日，全球自然科学三大旗舰期刊之首、英国《自然》正刊发表美国纽约纪念医院斯隆凯特林癌症中心、康奈尔大学威尔医学院、贝勒医学院、德克萨斯儿童医院、国家癌症研究所、弗雷德里克国家癌症研究实验室、意大利泰莱松遗传学与医学研究所、腓特烈二世大学的研究报告，发现肿瘤相关巨噬细胞可以通过饮食或基因重新编程击败癌基因MYC过度表达的乳腺癌细胞。 该研究首先利用乳腺癌小鼠模型发现，MYC过度表达可导致依赖于哺乳动物雷帕霉素靶蛋白复合体mTORC1信号传导的癌细胞在细胞竞争中成为获胜者。低蛋白质饮食可抑制癌细胞mTORC1信号传导并抑制肿瘤生长，这是由于肿瘤相关巨噬细胞转录因子TFEB和TFE3以及mTORC1被激活。大鼠肉瘤癌基因相关鸟苷酸三磷酸结合蛋白Rag通过鸟苷酸三磷酸酶激活mTORC1上游抑制因子GATOR1和FLCN可感知饮食来源的细胞质氨基酸，从而控制Rag鸟苷酸三磷酸酶效应分子，包括TFEB和TFE3。 在低蛋白质饮食条件下，抑制肿瘤相关巨噬细胞的GATOR1，可抑制TFEB、TFE3和mTORC1被激活，导致肿瘤生长加速；相反，在正常蛋白质饮食条件下，抑制肿瘤相关巨噬细胞的FLCN或Rag鸟苷酸三磷酸酶，可激活TFEB、TFE3和mTORC1，导致肿瘤生长减速。此外，肿瘤相关巨噬细胞和癌细胞的mTORC1过度激活及其竞争适应依赖于内溶酶体吞噬调节因子PIKfyve。 因此，该研究结果表明，肿瘤相关巨噬细胞通过非经典吞噬引起不依赖于Rag鸟苷酸三磷酸酶的mTORC1信号传导，可控制肿瘤相关巨噬细胞与癌细胞之间的竞争，这定义了一种新的先天免疫肿瘤抑制途径，可以作为乳腺癌治疗的新靶点，也为正常蛋白质饮食战胜乳腺癌奠定了基础，故有必要进一步开展临床研究进行验证。Nature. 2023 Jun 28. IF: 69.504Reprogramming tumour-associated macrophages to outcompete cancer cells.Xian Zhang, Shun Li, Isha Malik, Mytrang H. Do, Liangliang Ji, Chun Chou, Wei Shi, Kristelle J. Capistrano, Jing Zhang, Ting-Wei Hsu, Briana G. Nixon, Ke Xu, Xinxin Wang, Andrea Ballabio, Laura S. Schmidt, W. Marston Linehan, Ming O. Li.Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, USA; Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; National Cancer Institute, Bethesda, MD, USA; Frederick National Laboratory for Cancer Research, Frederick, MD, USA; Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; Federico II University, Naples, Italy.In metazoan organisms, cell competition acts as a quality control mechanism to eliminate unfit cells in favour of their more robust neighbours. This mechanism has the potential to be maladapted, promoting the selection of aggressive cancer cells. Tumours are metabolically active and are populated by stroma cells, 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 TFE3. 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
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