Scientists uncover why lungs particularly vulnerable to cancer development

The Brighter Side reveals in its recent article that recent research has uncovered groundbreaking insights into the role of aspartate in the development of lung metastases. 

Lung metastases are a harsh reality for more than half of cancer patients whose cancer has spread beyond its original site. These secondary tumors in the lungs form partly due to the distinct environment within the lungs.

Researchers have been working to uncover the mechanisms behind the aggressiveness of lung metastases, with recent discoveries highlighting the amino acid aspartate as a crucial factor.

The structure and biochemistry of the lungs make them an ideal location for metastasis. Their extensive network of blood vessels helps trap circulating cancer cells, while the less oxidative environment provides a safer space for these cells to thrive.

Another significant factor is the lungs' ability to create a pre-metastatic niche—a supportive environment influenced by tumor-secreted factors (TSFs) from primary tumors.

These TSFs alter lung immune cells and the extracellular matrix, preparing the lungs for the arrival of cancer cells. Additionally, they increase the availability of specific nutrients in the lung interstitial fluid, which directly impacts the behavior of cancer cells. Among these nutrients, aspartate has emerged as a key player in the process.

Aspartate's unique role in cancer metastasis has captured the attention of scientists. Unlike other nutrients that need to be directly absorbed by cells, aspartate functions as a signaling molecule, a discovery that challenges traditional views of how nutrients influence cancer progression.

Typically scarce in blood plasma, aspartate was found in unexpectedly high concentrations in the lung interstitial fluid of both mice and patients with metastatic breast cancer. This elevated level was not present in mice with non-metastatic primary breast tumors or in other organs, suggesting a distinct link between aspartate and lung metastases.

To delve deeper, researchers pre-treated mice with aspartate before introducing breast cancer cells. Published in Nature, this pre-treatment mimicked the high aspartate levels seen in metastatic lungs, leading to increased aggressiveness of the metastases and heightened activity of the protein eIF5A, which plays a crucial role in protein synthesis.

“We found high levels of aspartate in the lungs of mice and patients with breast cancer compared to those without cancer,” says Ginevra Doglioni, lead author of the study. “This suggests that aspartate may be crucial for lung metastasis.”

Aspartate's impact on metastases involves a complex signaling cascade. Unlike most nutrients that enter cancer cells via transport mechanisms, aspartate behaves differently by binding to NMDA receptors on the surface of cancer cells.

This binding activates intracellular signaling pathways that stimulate the expression of deoxyhypusine hydroxylase (DOHH), an enzyme crucial for modifying eIF5A through a process known as hypusination.

Once eIF5A is hypusinated, it triggers a translational program that boosts the ability of cancer cells to thrive in the lung environment. This program includes enhanced collagen synthesis and TGFβ signaling, which remodel the extracellular matrix to support aggressive tumor growth.

This discovery underscores how cancer cells utilize existing biochemical pathways to adapt and thrive in new environments. Aspartate’s function as a signaling molecule, rather than just a nutrient, marks a significant shift in our understanding of metastatic progression.

By Naila Huseynova