More than half of patients with cancer that ends up spreading beyond the place where it starts have lung metastases. What makes the lungs such a tempting place for cancer cells? To find out, the team of Professor Sarah-Maria Fendt (VIB-KU Leuven Center for Cancer Biology) and her colleagues investigated gene expression in cells from aggressive lung metastases. They found evidence 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 allow cancer cells to grow more easily in the pulmonary environment.
But what initiates this alternative translational program in aggressive metastases? «We found high levels of aspartate in the lungs of mice and patients with breast cancer compared to mice and patients without cancer, suggesting that aspartate may be important for lung metastasis,” says Ginevra Doglioni, a doctoral student in the Fendt laboratory and first author of the study.
Aspartate is an amino acid (a building block of proteins) that has very low concentrations in blood plasma but, surprisingly, very high concentrations in the lungs of mice with metastatic breast cancer.
Many proteins in our body can affect the translation process, including the so-called initiation factors. One of them is eIF5A, which triggers translation. In cancer cells from lung metastases, the researchers found an activating modification of eIF5A called “hypusination,” which was associated with a increased cancer aggressiveness in lung metastases.
Does aspartate have anything to do with this? Yes that’s how it is. The researchers discovered that aspartate triggered this modification in eIF5A through an unexpected mechanism. Surprisingly, the aspartate was not absorbed by the cancer cells. Instead, it activated a cell surface protein called NMDA receptor in cancer cells, leading to a signaling cascade which ultimately triggered the hypusination of eIF5A. This subsequently drives a translation program that improves the ability of cancer cells to change their environment and make it more suitable for aggressive growth.
Looking at human lung tumor samples from patients with metastatic breast cancer, the scientists observed a translational program similar to that in mice and elevated expression of the aspartate-binding subunit of the NMDA receptor compared to metastases from other organs. .
“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 lung. Furthermore, there are drugs available to act on the mechanism we have identified and therefore, with more research, it could be possible to translate it into the clinical setting,” says Professor Fendt.
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