New Study Uncovers Why Cancer Often Spreads to the Lungs

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.

Hence a recent study 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, the authors observed 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). Deoxyhypusine hydroxylase 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.

The researchers detected key proteins of this mechanism in lung metastases from patients with breast cancer.

Therefore, they concluded that aspartate, a classical biosynthesis metabolite, functions in the lung environment as an extracellular signalling molecule to promote aggressiveness of metastases.

Ref: Doglioni, G., Fernández-García, J., Igelmann, S. et al. Aspartate signalling drives lung metastasis via alternative translation. Nature (2025). https://doi.org/10.1038/s41586-024-08335-7