Aspartate signalling drives lung metastasis via alternative translation.

Autor:	Doglioni G; Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium., Fernández-García J; Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium., Igelmann S; Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium., Altea-Manzano P; Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.; Laboratory of Metabolic Regulation and Signaling in Cancer, Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER)-University of Seville-CSIC-University Pablo de Olavide, Seville, Spain., Blomme A; Laboratory of Cancer Signaling, GIGA-Institute, University of Liège, Liège, Belgium., La Rovere R; Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium., Liu XZ; Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium., Liu Y; Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.; Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China., Tricot T; Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium., Nobis M; Laboratory of Intravital Microscopy and Dynamics of Tumor Progression, VIB Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Intravital Microscopy and Dynamics of Tumor Progression, Department of Oncology, KU Leuven, Leuven, Belgium.; Intravital Imaging Expertise Center, VIB Center for Cancer Biology, VIB, Leuven, Belgium., An N; Laboratory of Cancer Signaling, GIGA-Institute, University of Liège, Liège, Belgium., Leclercq M; Laboratory of Cancer Signaling, GIGA-Institute, University of Liège, Liège, Belgium., El Kharraz S; Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium., Karras P; Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium., Hsieh YH; Leibniz Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany., Solari FA; Leibniz Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany., Martins Nascentes Melo L; Department of Dermatology, University Hospital Essen and German Cancer Consortium, Essen, Germany., Allies G; Department of Dermatology, University Hospital Essen and German Cancer Consortium, Essen, Germany., Scopelliti A; Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium., Rossi M; Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium., Vermeire I; Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium., Broekaert D; Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium., Ferreira Campos AM; Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium., Neven P; Department of Gynaecology and Obstetrics, UZ Leuven, Leuven, Belgium., Maetens M; Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium., Van Baelen K; Department of Gynaecology and Obstetrics, UZ Leuven, Leuven, Belgium.; Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium., Alkan HF; Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.; Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA., Planque M; Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.; Spatial Metabolomics Expertise Center, VIB Center for Cancer Biology, VIB, Leuven, Belgium., Floris G; Department of Pathology, UZ Leuven, Leuven, Belgium.; Department of Imaging and Pathology, Laboratory of Translational Cell And Tissue Research, KU Leuven, Leuven, Belgium., Sickmann A; Leibniz Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany.; Medizinische Fakultät, Medizinische Proteom-Center (MPC), Ruhr-Universität Bochum, Bochum, Germany., Tasdogan A; Department of Dermatology, University Hospital Essen and German Cancer Consortium, Essen, Germany., Marine JC; Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium., Scheele CLGJ; Laboratory of Intravital Microscopy and Dynamics of Tumor Progression, VIB Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Intravital Microscopy and Dynamics of Tumor Progression, Department of Oncology, KU Leuven, Leuven, Belgium., Desmedt C; Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium., Bultynck G; Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium., Close P; Laboratory of Cancer Signaling, GIGA-Institute, University of Liège, Liège, Belgium.; WELBIO Department, WEL Research Institute, Wavre, Belgium., Fendt SM; Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium. sarah-maria.fendt@kuleuven.be.; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium. sarah-maria.fendt@kuleuven.be.
Jazyk:	angličtina
Zdroj:	Nature [Nature] 2025 Jan 01. Date of Electronic Publication: 2025 Jan 01.
DOI:	10.1038/s41586-024-08335-7
Abstrakt:	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 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. Competing Interests: Competing interests: S.-M.F. has received funding from BlackBelt Therapeutics, Auron Therapeutics, Gilead and Alesta Therapeutics, is on the advisory board of Alesta Therapeutics and has consulted for Fund+ and Droia Ventures. The other authors declare no competing interests. (© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze:	MEDLINE
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