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肺是各种癌症的常见转移器官，高达54%的晚期癌症患者发生肺转移。根据中国医学科学院肿瘤医院对1999年至2009年3569例肺转移肿瘤原发部位的调查分析，原发于肺以外肿瘤出现肺转移最多的是乳腺癌，占16.92%。肺之所以成为肿瘤全身转移发生率最高的脏器，主要由于肺是体循环的第一过滤部位、全身血流的必经之路；其次，肺循环是低压系统，血流缓慢，癌细胞易于停滞；加之肺接受肺动脉和支气管动脉的双重血管供应，血供营养丰富，使癌细胞的肺部转移率增大。此外，原发肿瘤分泌的因子可改变免疫细胞和肺细胞外基质，为癌细胞的到来创造适宜的转移前环境。营养物质也可在转移前微环境形成过程中做好准备。不过，肿瘤转移器官可用的营养物质是否以及如何赋予癌细胞转移特征尚不明确。 2025年1月1日，全球自然科学三大旗舰期刊之首、创刊155周年的英国《自然》正刊在线发表比利时法兰德斯生物技术研究院癌症生物学中心、荷兰语天主教鲁汶大学癌症研究所、列日大学、鲁汶大学医院、瓦夫尔研究院、中国江苏大学附属医院、德国癌症联盟、莱布尼茨分析科学研究院、埃森大学医院、波鸿鲁尔大学医学院的研究报告，首次发现天门冬氨酸可触发肺转移癌细胞信号传导连锁反应，从而产生增强肺转移侵袭性的蛋白质生物合成。 天门冬氨酸简称天冬氨酸，药学又称门冬氨酸，是构成人体蛋白质的20种氨基酸之一，普遍存在于生物合成过程，最初被发现于天门冬科天门冬属植物芦笋，故以其英文名称命名为天门冬氨酸。对于人类，天冬氨酸属于非必需氨基酸，可经转氨基作用从草酰乙酸转化，再经转氨基作用可转化为另一种非必需氨基酸天门冬酰胺。天门冬氨酸和天门冬酰胺主要用于合成甜味剂，还被作为肝功能促进剂、氨解毒剂、疲劳消除剂和氨基酸输液成分等，门冬氨酸钾镁还被用于治疗低血钾症以及洋地黄中毒引起的心律失常。常用人工甜味剂阿斯巴甜（天门冬胺酰苯丙氨酸甲酯）也可被人体代谢为天门冬氨酸、苯丙氨酸和甲醇。 该研究首先观察到乳腺癌患者、三阴性乳腺癌4T1和EMT6.5小鼠肺间质液天门冬氨酸浓度较高，该细胞外天门冬氨酸可激活癌细胞离子型N-甲基-d-天门冬氨酸（NMDA）受体从而促进依赖于环磷腺苷效应元件结合蛋白（CREB）的脱氧羟丁酸羟化酶（DOHH）表达。DOHH对于羟丁酸化至关重要，羟丁酸化是基因转录翻译为蛋白质后的化学修饰步骤之一，是非经典真核翻译起始因子eIF5A活性所必需的。反之，以转化生长因子TGFβ信号传导为中心枢纽的翻译程序，可促进乳腺癌肺转移细胞的胶原蛋白合成。最后，该研究在乳腺癌患者肺转移灶检测到该机制的上述关键蛋白质。天门冬氨酸通过诱导eIF5A羟丁酸化作用促进肺转移侵袭性 因此，该研究结果表明，经典的生物合成代谢产物之一天门冬氨酸在肺环境中可作为细胞外信号传导分子发挥作用，从而促进乳腺癌肺转移，该机制关键蛋白质有望成为新的治疗靶点，故有必要进一步开展临床研究进行验证。Nature. 2025 Jan 1. IF: 50.5 Aspartate signalling drives lung metastasis via alternative translation. Doglioni G, Fernández-García J, Igelmann S, Altea-Manzano P, Blomme A, La Rovere R, Liu XZ, Liu Y, Tricot T, Nobis M, An N, Leclercq M, El Kharraz S, Karras P, Hsieh YH, Solari FA, Martins Nascentes Melo L, Allies G, Scopelliti A, Rossi M, Vermeire I, Broekaert D, Ferreira Campos AM, Neven P, Maetens M, Van Baelen K, Alkan HF, Planque M, Floris G, Sickmann A, Tasdogan A, Marine JC, Scheele CLGJ, Desmedt C, Bultynck G, Close P, Fendt SM. VIB Center for Cancer Biology, VIB, Leuven, Belgium; KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium; University of Liège, Liège, Belgium; UZ Leuven, Leuven, Belgium; WEL Research Institute, Wavre, Belgium; Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China; Leibniz Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany; University Hospital Essen and German Cancer Consortium, Essen, Germany; Medizinische Fakultat, Medizinische Proteom-Center (MPC), Ruhr-Universitat Bochum, Bochum, Germany. Lung metastases occur in up to 54% of patients with metastatic tumours. Contributing factors to this high frequency include the physical properties of the pulmonary system and a less oxidative environment that may favour the survival of cancer cells. Moreover, secreted factors from primary tumours alter immune cells and the extracellular matrix of the lung, creating a permissive pre-metastatic environment primed for the arriving cancer cells. Nutrients are also primed during pre-metastatic niche formation. Yet, whether and how nutrients available in organs in which tumours metastasize confer cancer cells with aggressive traits is mostly undefined. Here we found that pulmonary aspartate triggers a cellular signalling cascade in disseminated cancer cells, resulting in a translational programme that boosts aggressiveness of lung metastases. Specifically, we observe that patients and mice with breast cancer have high concentrations of aspartate in their lung interstitial fluid. This extracellular aspartate activates the ionotropic N-methyl-d-aspartate receptor in cancer cells, which promotes CREB-dependent expression of deoxyhypusine hydroxylase (DOHH). DOHH is essential for hypusination, a post-translational modification that is required for the activity of the non-classical translation initiation factor eIF5A. In turn, a translational programme with TGFβ signalling as a central hub promotes collagen synthesis in lung-disseminated breast cancer cells. We detected key proteins of this mechanism in lung metastases from patients with breast cancer. In summary, we found that aspartate, a classical biosynthesis metabolite, functions in the lung environment as an extracellular signalling molecule to promote aggressiveness of metastases. PMID: 39743589 DOI: 10.1038/s41586-024-08335-7
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