Aspartate signalling drives lung metastasis via alternative translation

• 成果类型: Article
• 署名作者: Doglioni, Ginevra; Fernandez-Garcia, 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, Melanie; Floris, Giuseppe; Sickmann, Albert; Tasdogan, Alpaslan; Marine, Jean-Christophe; Scheele, Colinda L. G. J.; Desmedt, Christine; Bultynck, Geert; Close, Pierre; Fendt, Sarah-Maria
• 署名单位: Flanders Institute for Biotechnology (VIB); KU Leuven; University of Liege; KU Leuven; Jiangsu University; Flanders Institute for Biotechnology (VIB); KU Leuven; Flanders Institute for Biotechnology (VIB); Flanders Institute for Biotechnology (VIB); KU Leuven; Dortmund University of Technology; Leibniz Association; Leibniz Institut fur Analytische Wissenschaften (ISAS); University of Duisburg Essen; Helmholtz Association; German Cancer Research Center (DKFZ); KU Leuven; University Hospital Leuven; KU Leuven; Flanders Institute for Biotechnology (VIB); KU Leuven; University Hospital Leuven; KU Leuven; Ruhr University Bochum; Universidad Pablo de Olavide; University of Sevilla; Consejo Superior de Investigaciones Cientificas (CSIC); University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1019
• DOI: 10.1038/s41586-024-08335-7
• 发表日期: 2025-02-01
• 页码: 244-+
• 关键词: cancer; expression; plasticity; GROWTH

摘要

Lung metastases occur in up to 54% of patients with metastatic tumours(1,2). 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 cells(3). 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(4,5). Nutrients are also primed during pre-metastatic niche formation(6). 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 TGF beta 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.