Cancer cells can either originate in the lung – this is called primary lung cancer – and metastasize to other organs, or reach the lung from another primary site (pulmonary metastases). The term metastasis refers to the migration of cancer cells from a primary tumor to a secondary site.
A very recent discovery, published in the journal Nature, opens the way to new therapeutic interventions against metastatic spread. Researchers have indeed identified a key element favoring the implantation of aggressive cancer cells in lung tissue. It is an amino acid: aspartate.
One in two cancer patients with metastases develops them in the lung
The lungs are often the site of metastases. Some studies even estimate that lung metastases are present in 54% of patients with metastatic tumors. This high frequency is explained by the physical properties of the pulmonary system (after passing through the venous circulation, the circulating tumor cells take the venous system which converges towards the right heart, before being propelled into the pulmonary circulation). Another complementary mechanism would be the less oxidative environment in the lung, which could promote the survival of cancer cells. Oxidation is a chemical reaction in which molecules lose electrons, often due to interaction with oxygen. The consequence is the production of unstable chemical species called free radicals, which can damage cells and tissues.
In addition, factors secreted by the primary tumors themselves modify the immune cells and the extracellular matrix* of the lung, creating an environment conducive to the establishment of cancer cells that reach them. However, the way in which nutrients present in the organs targeted by metastases give cancer cells aggressive characteristics remains poorly defined. This new study shows that one of these nutrients, the amino acid aspartate, present in the lung, triggers a cascade of cellular signals in disseminated cancer cells, thus increasing the aggressiveness of these lung metastases.
Aspartate may play a key role in lung metastases
More specifically, Professor Fendt’s team (VIB-KU Leuven Cancer Biology Center) observed that breast cancer patients and mice had high concentrations of aspartate in their pulmonary interstitial fluid. This extracellular aspartate activates a specific receptor located on cancer cells (ionotropic N-methyl-D-aspartate), which triggers a cascade process making metastatic tumors in the lung aggressive. In summary, this key protein, essential for the proper functioning of our cells, is misused: it behaves in the pulmonary environment like a signaling molecule present outside the cells to promote the aggressiveness of metastatic cancer cells disseminated in the lungs. lungs.
By what mechanism?
If the scientists went in this direction and were able to identify the mechanisms involved, it was because they had observed “high levels of aspartate in the lungs of mice and patients with breast cancer compared to those without cancer, comments Ginevra Doglioni, doctoral student at the Fendt laboratory and first author of the study. This suggested that aspartate might play a key role in lung metastases. »
Researchers observed an activating modification of a factor (eIF5A) in lung metastases cancer cells, associated with increased aggressiveness of lung metastases. However, they were able to demonstrate that aspartate triggered this modification of eIF5A.
Professor Fendt emphasizes: “ Signaling (activation, editor’s note) by aspartate could be a common characteristic of cancer cells colonizing the lungs. Furthermore, there are already drugs capable of targeting this mechanism. With additional research, clinical application could be possible. »
* complex network of complex proteins and sugars that provides structural support to lung cells and plays a crucial role in regulating various biological functions
Source : Doglioni, G., Fernández-García, J., Igelmann, S. et al. Aspartate signaling drives lung metastasis via alternative translation. Nature (2025). https://doi.org/10.1038/s41586-024-08335-7; Gerull, WD, Puri, V. & Kozower, BD The epidemiology and biology of pulmonary metastases. J. Thorac. This. 13, 2585–2589 (2021).
