Aspartate Sparks Cancer’s Leap to the Lungs

Researchers have discovered why the lungs are often targeted by metastasizing cancer cells, pinpointing the amino acid aspartate as a key player.

This breakthrough provides insight into the genetic changes that enable cancer to thrive in the lung environment, offering potential new avenues for treatment.

The Role of Aspartate in Lung Metastasis

More than half of cancer patients with metastatic disease develop lung metastases. But why are the lungs such an attractive environment for cancer cells?

To explore this, Prof. Sarah-Maria Fendt’s team at the VIB-KU Leuven Center for Cancer Biology studied gene expression in cells from aggressive lung metastases. Their research revealed the presence of an alternative “translation program.” This refers to a shift in the process by which genetic information is used to produce proteins. Such changes result in a different set of proteins that enable cancer cells to thrive more easily in the lung environment.

But what starts this alternative translational program in aggressive metastases?

Ginevra Doglioni, PhD student at the Fendt lab and first author of the study says “We found high levels of aspartate in the lungs of mice and patients with breast cancer compared to mice and patients without cancer, which suggests that aspartate may be important for lung metastasis.”

Aspartate is an amino acid (a protein building block) that has very low concentrations in blood plasma but, surprisingly, very high concentrations in the lungs of mice with metastatic breast cancer.

Triggering Cancer’s Aggressive Growth

Many proteins in our bodies can affect the translation process, among them the so-called initiation factors. One such initiation factor is eIF5A, which kickstarts translation. In the cells of cancer cells within lung metastases, the researchers found an activating modification to eIF5A called ‘hypusination’, which was associated with higher cancer aggressiveness of lung metastases.

Does aspartate have something to do with this?

Yes, it does! The researchers discovered that aspartate triggered this modification on eIF5A through an unexpected mechanism. Surprisingly, aspartate was not taken up by the cancer cells. Instead, it activated a cell surface protein called an NMDA receptor in cancer cells, leading to a signaling cascade that, eventually, triggered eIF5A hypusination. This subsequently drives a translational program that enhances the ability of cancer cells to change their environment and make it more suitable for aggressive growth.

Clinical Implications and Future Directions

Looking at human lung tumor samples from patients with metastatic breast cancer, the scientists noted a similar translational program as in mice and an elevated expression of the NMDA receptor subunit that binds aspartate compared to metastases from other organs.

Prof. Fendt explains, “This correlation emphasizes 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. Moreover, there are drugs available to target the mechanism we identified and thus with further research a translation toward a clinical setting might be possible.”

Reference: “Aspartate signalling drives lung metastasis via alternative translation” by Ginevra Doglioni, Juan Fernández-García, Sebastian Igelmann, Patricia Altea-Manzano, Arnaud Blomme, Rita La Rovere, Xiao-Zheng Liu, Yawen Liu, Tine Tricot, Max Nobis, Ning An, Marine Leclercq, Sarah El Kharraz, Panagiotis Karras, Yu-Heng Hsieh, Fiorella A. Solari, Luiza Martins Nascentes Melo, Gabrielle Allies, Annalisa Scopelliti, Matteo Rossi, Ines Vermeire, Dorien Broekaert, Ana Margarida Ferreira Campos, Patrick Neven, Marion Maetens, Karen Van Baelen, H. Furkan Alkan, Mélanie Planque, Giuseppe Floris, Albert Sickmann, Alpaslan Tasdogan, Jean-Christophe Marine, Colinda L. G. J. Scheele, Christine Desmedt, Geert Bultynck, Pierre Close and Sarah-Maria Fendt, 1 January 2025, Nature.
DOI: 10.1038/s41586-024-08335-7

This research was supported by FWO, Kom Op Tegen Kanker, Stichting tegen Kanker, Beug Foundation, King Baudouin Foundation, Fonds Baillet Latour, Francqui Stichting, Foundation ARC, and KU Leuven.

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