 Aspartate signalling drives lung metastasis via alternative translationGinevra Doglioni,
Juan Fernández-García,
Sebastian Igelmann,
Patricia Altea-Manzano,
Arnaud Blomme,
Rita Rovere,
Xiao-Zheng Liu,
Yawen Liu,
Tine Tricot,
Max Nobis,
Ning An,
Marine Leclercq,
Sarah El Kharraz,
Panagiotis Karras,
Yu-Heng Hsieh,
Fiorella A. Solari,
Luiza Martins Nascentes Melo,
Gabrielle Allies,
Annalisa Scopelliti,
Matteo Rossi,
Ines Vermeire,
Dorien Broekaert,
Ana Margarida Ferreira Campos,
Patrick Neven,
Marion Maetens,
Karen Baelen,
H. Furkan Alkan,
Mélanie Planque,
Giuseppe Floris,
Albert Sickmann,
Alpaslan Tasdogan,
Jean-Christophe Marine,
Colinda L. G. J. Scheele,
Christine Desmedt,
Geert Bultynck,
Pierre Close and
Sarah-Maria Fendt ()
Nature, 2025, vol. 638, issue 8049, 244-250 Abstract: 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. Date: 2025 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:638:y:2025:i:8049:d:10.1038_s41586-024-08335-7 Ordering information: This journal article can be ordered from DOI: 10.1038/s41586-024-08335-7 Access Statistics for this article Nature is currently edited by Magdalena Skipper More articles in Nature from Nature |
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