A new study has identified one of the reasons why cancer frequently spreads from elsewhere in the body to the lungs: an amino acid called aspartate. The findings improve our understanding of cancer and open the door to new treatments for metastatic disease.
Over half of the patients whose cancer spreads from its site of origin will develop metastases, or secondary tumors, in the lung. It’s known that cancer cells are transported from one part of the body to the lungs via arteries and lymphatic vessels. What is less well known is why cancer cells find the lungs so attractive.
A new study by researchers from the Vlaams Instituut voor Biotechnologie (VIB)-KU Leuven Center for Cancer Biology (CCB), Belgium, has identified one reason lung metastases are so common: an amino acid called aspartate.
“We found high levels of aspartate in the lungs of mice and patients with breast cancer compared to mice and mice patients without cancer, which suggests that aspartate may be important for lung metastasis,” said Ginevra Doglioni, a PhD student at the CCB and the study’s lead author.
Aspartate plays important roles in the body, including in the lungs. As an amino acid, it’s one of the building blocks of proteins, crucial to the structure and function of lung cells. Additionally, it’s involved in energy production, pH level maintenance, and immune support, all of which are vital for healthy respiratory function.
Translation is the biological process where genetic information is used to build proteins. The following is a simplified account of how this occurs. DNA is transcribed into messenger RNA (mRNA). mRNA carries the genetic code to the ribosome, the cell’s protein-making machinery. Ribosomes read the mRNA sequence, and as the ribosome moves along the mRNA, amino acids are linked together in the order specified, forming a growing protein chain. A change in the translational instructions, or program, results in the production of a different set of proteins that allow the growth of cancer cells.
Eukaryotic translation initiation factor 5A (eIF-5A) is a protein that helps cells efficiently make other proteins, playing a key role in two translation stages: initiation and elongation (helping ribosomes move along the mRNA and add amino acids to the protein chain). Specifically, eIF-5A helps when the ribosome encounters challenging parts of mRNA, which would otherwise cause the ribosome to stall. eIF-5A contains a unique amino acid called hypusine. Hypusine is essential to eIF-5A; without it, it can’t assist the ribosome. The production of hypusine via a chemical reaction is called hypusination.
To investigate what promoted secondary cancer growth in the lungs, the researchers performed single-cell RNA sequencing of metastases growing in healthy lungs and in lungs primed with tumor-growth-promoting factors produced by breast cancer cells. The latter resulted in more aggressive metastatic disease.
The researchers observed that patients and mice with breast cancer had high concentrations of aspartate in their interstitial fluid, the fluid that fills the spaces between the air sacs and surrounding blood vessels in the lungs. They also found that lung aspartate activated the N-methyl-D-aspartate (NMDA) receptor on the surface of the cancer cells, which promoted eIF5A hypusination and an alternative translation program that resulted in increased aggressiveness in the metastases.
“This correlation emphasizes the relevance of the findings in a clinical context and suggests that aspartate signaling may be a common feature of cancer cell growing in the lung,” said Professor Sarah-Maria Fendt, a principal investigator at the CCB and the study’s corresponding author.
The researchers say that their findings have improved our understanding of cancer biology and opened the door to developing a new treatment for metastatic disease.
The study was published in the journal Nature.
Source: VIB-KU Leuven CCB via EurekAlert!
