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
