Researchers from KULeuven and ULiège have discovered that the availability of the amino acid aspartate is one of the reasons why the lung is a frequent organ of metastases. Their work, published in Natureimprove our understanding of cancer biology and lay the foundation for new therapeutic interventions in metastatic disease.
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More than half of patients with cancer that spreads beyond the primary site have lung metastases. What makes the lungs such a tempting place for cancer cells?
To find out, the teams of Professor Sarah-Maria Fendt (VIB-KULeuven Center for Cancer Biology) and Professor Pierre Close (ULiège, GIGA, Lab of Cancer Signaling) studied the expression of genes in the cells of aggressive lung metastases. . They found evidence of the existence of an alternative “translation program.” 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 program results in a set of different proteins that make it easier for cancer cells to grow in the lung environment.
But what triggers this alternative translation program in aggressive metastases?
Ginevra Doglioni, doctoral student in Professor Fendt’s laboratory and first author of the study, declares: “ We found elevated levels of aspartate in the lungs of mice and breast cancer patients compared to mice and patients without cancer, suggesting that aspartate may be important for lung metastases. »
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.
Start of the translational program
Many proteins present in our body can influence the translation process, in particular the so-called initiation factors. One of these initiation factors is eIF5A, which kickstarts translation. In lung metastasis cancer cells, researchers discovered an activating modification of eIF5A called “hypusination,” which was associated with greater lung metastasis cancer aggressiveness.
Is aspartate involved? Yes, it is. Indeed, the researchers discovered that aspartate triggered this modification of eIF5A by an unexpected mechanism. Surprisingly, aspartate was not taken up by cancer cells. Rather, it activated a cell surface protein called the NMDA receptor in cancer cells, leading to a signaling cascade that ultimately triggered hypusination of eIF5A. The latter then drives a translation program that enhances the ability of cancer cells to modify their environment and make it more conducive to aggressive growth.
By examining human lung tumor samples from patients with metastatic breast cancer, scientists observed a translation program similar to that of mice and high expression of the NMDA receptor subunit that binds aspartate compared to metastases to other organs.
Professor Fendt explains: “ This correlation highlights the relevance of the findings in a clinical context and suggests that aspartate signaling may be a common feature of cancer cells growing in the lungs. Furthermore, there are drugs that target the mechanism we identified and, therefore, further research could translate this 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 recognized expertise in the study of translation regulation, the team of Professor Pierre Close, WELBIO-FNRS investigator, used cutting-edge technologies to decipher the precise molecular mechanisms. These mechanisms allow lung cancer cells to exploit aspartate as a pro-metastatic agent, notably by modulating the alternative translation of mRNAs.
Scientific reference
Doglioni, G., Fernández-García, J., Igelmann,S. et al., Aspartate signaling drives lung metastasis via alternative translation. Doglioni et al. Nature, 2024. DOI 10.1038/s41586-024-08335-7.
This research was supported by FWO, FNRS, 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.
Contact
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