比利时鲁汶大学癌症生物学中心Sarah-Maria Fendt研究小组发现，天冬氨酸信号通过可变翻译驱动肺转移。2025年1月1日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员发现肺部天冬氨酸触发了扩散癌细胞中的细胞信号级联反应，导致一个翻译程序，增强了肺转移的侵袭性。具体来说，研究人员观察到患有乳腺癌的患者和小鼠在其肺间质液中具有较高浓度的天冬氨酸。

这种细胞外天冬氨酸激活了癌细胞中的离子型N-甲基-D-天冬氨酸受体，促进了CREB依赖性的脱氧假尿苷羟化酶（DOHH）表达。DOHH对假尿苷化至关重要，这是一种必需的翻译后修饰，作用于非经典翻译起始因子eIF5A的活性。反过来，以TGFβ信号传导为中心的翻译程序促进了肺部分散乳腺癌细胞的胶原合成。

研究人员在乳腺癌患者的肺转移中检测到了这一机制的关键蛋白。总之，研究人员发现天冬氨酸，作为一种经典的生物合成代谢物，在肺部环境中作为一种细胞外信号分子，促进了转移的侵袭性。

据了解，肺转移发生在高达54%的转移性肿瘤患者中。导致这一高频率的因素包括肺系统的物理特性和较少的氧化环境，这可能有利于癌细胞的生存。

此外，来自原发肿瘤的分泌因子改变了免疫细胞和肺部细胞外基质，创造了一个有利的前转移环境，为到达的癌细胞做好准备。营养物质在前转移微环境形成过程中也会被预先准备。然而，肿瘤转移的器官中可用的营养物质是否以及如何赋予癌细胞侵袭性特征，仍然大部分未被定义。

附：英文原文

Title: Aspartate signalling drives lung metastasis via alternative translation

Author: Doglioni, Ginevra, Fernndez-Garca, Juan, Igelmann, Sebastian, Altea-Manzano, Patricia, Blomme, Arnaud, La Rovere, Rita, Liu, Xiao-Zheng, Liu, Yawen, Tricot, Tine, Nobis, Max, An, Ning, Leclercq, Marine, El Kharraz, Sarah, Karras, Panagiotis, Hsieh, Yu-Heng, Solari, Fiorella A., Martins Nascentes Melo, Luiza, Allies, Gabrielle, Scopelliti, Annalisa, Rossi, Matteo, Vermeire, Ines, Broekaert, Dorien, Ferreira Campos, Ana Margarida, Neven, Patrick, Maetens, Marion, Van Baelen, Karen, Alkan, H. Furkan, Planque, Mlanie, Floris, Giuseppe, Sickmann, Albert, Tasdogan, Alpaslan, Marine, Jean-Christophe, Scheele, Colinda L. G. J., Desmedt, Christine, Bultynck, Geert, Close, Pierre, Fendt, Sarah-Maria

Issue&Volume: 2025-01-01

Abstract: Lung metastases occur in up to 54% of patients with metastatic tumours1,2. 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 cells3. 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 cells4,5. Nutrients are also primed during pre-metastatic niche formation6. 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.

DOI: 10.1038/s41586-024-08335-7

Source: https://www.nature.com/articles/s41586-024-08335-7