Researchers at KULeuven and ULiège have discovered that the availability of the amino acid aspartate is one of the reasons why the lung is a frequent metastasis organ. Their work, published in Nature, improves our understanding of cancer biology and lays the foundations for new therapeutic interventions in metastatic diseases.
M
ore than half of patients with cancer that spreads beyond the primary site develop lung metastases. What makes the lungs such a tempting place for cancer cells?
To find out, teams led by Prof. Sarah-Maria Fendt (VIB-KULeuven Center for Cancer Biology) and Prof. Pierre Close (ULiège, GIGA Research Center, Lab of Cancer Signaling) studied gene expression in cells from aggressive lung metastases. They found evidence of the existence of an alternative ‘translation programme’. What does this mean? Translation is the process that uses our genetic code as a blueprint for making proteins in cells. A change in the translation programme results in a different set of proteins that make it easier for cancer cells to grow in the lung environment.
But what triggers this alternative translation programme in aggressive metastases?
Ginevra Doglioni, a PhD researcher in Professor Fendt's laboratory and first author of the study, says: ‘ We found elevated levels of aspartate in the lungs of mice and patients with breast cancer compared with mice and patients without cancer, suggesting that aspartate may be important for lung metastasis.’
Aspartate is an amino acid (a building block of proteins) whose concentrations are very low in blood plasma but, surprisingly, very high in the lungs of mice with metastatic breast cancer.
Launch of the translational programme
Many proteins present in our bodies can influence the translation process, in particular so-called initiation factors. One of these initiation factors is eIF5A, which initiates translation. In lung metastatic cancer cells, the researchers discovered an activating modification of eIF5A called ‘hypusination’, which was associated with greater aggressiveness of lung metastatic cancer.
Is aspartate involved? Yes, it is. In fact, the researchers discovered that aspartate triggered this modification of eIF5A by an unexpected mechanism. Surprisingly, the aspartate was not absorbed by the cancer cells. Instead, it activated a cell surface protein called the NMDA receptor in the cancer cells, leading to a signalling cascade that ultimately triggered hypusination of eIF5A. This in turn leads to a translation programme that enhances the ability of cancer cells to modify their environment and make it more conducive to aggressive growth.
By examining samples of human lung tumours from patients with metastatic breast cancer, the scientists observed a translation programme similar to that in mice and a higher expression of the NMDA receptor subunit that binds aspartate than in metastases from other organs.
Prof. Fendt explained: ‘This correlation underlines the relevance of the results in a clinical context and suggests that aspartate signalling could be a common feature of cancer cells that develop in the lungs. In addition, there are drugs available that target the mechanism we have identified and, therefore, further research could enable it to be translated into a clinical context.’
As part of this study, the GIGA team played a key role in characterizing the translational reprogramming responsible for the adaptation of cancer cells and the formation of metastases in response to aspartate. With recognised expertise in studying the regulation of translation, the team of Prof. Pierre Close, WELBIO-FNRS investigator, leveraged advanced technologies to unravel the precise molecular mechanisms. These mechanisms enable lung cancer cells to exploit aspartate as a pro-metastatic agent, particularly by modulating the alternative translation of mRNAs.
Doglioni, G., Fernández-García, J., Igelmann, S.& al., Aspartate signaling drives lung metastasis via alternative translation, Nature, 2025. DOI 10.1038/s41586-024-08335-7.
This research was supported by FWO, FNRS Fund For Scientific Research, Kom Op Tegen Kanker, Fondation contre le cancer, Beug Foundation, King Baudouin Foundation, Fonds Baillet Latour, Fondation Francqui, Foundation ARC, WELRI-WELBIO Advanced, KU Leuven & ULiège.
The ULiège researchers involved in this study: Pierre Close, Arnaud Blomme, Ning An & Marine Leclercq.
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