Cancer's frequent spread to the lungs is driven by important amino acid aspartate

Cancer is history (soon)!

"... Over half of the patients whose cancer spreads from its site of origin will develop metastases, or secondary tumors, in the lung. ...

A new study by researchers ... has identified one reason lung metastases are so common: an amino acid called aspartate. ...

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. ...

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. ..."

From the abstract:

"Lung metastases occur in up to 54% of patients with metastatic tumours. Contributing factors to this high frequency include the physical properties of the pulmonary system and a less oxidative environment that may favour the survival of cancer cells. Moreover, secreted factors from primary tumours alter immune cells and the extracellular matrix of the lung, creating a permissive pre-metastatic environment primed for the arriving cancer cells. Nutrients are also primed during pre-metastatic niche formation. Yet, whether and how nutrients available in organs in which tumours metastasize confer cancer cells with aggressive traits is mostly undefined.

Here we found that pulmonary aspartate triggers a cellular signalling cascade in disseminated cancer cells, resulting in a translational programme that boosts aggressiveness of lung metastases. Specifically, we observe that patients and mice with breast cancer have high concentrations of aspartate in their lung interstitial fluid. This extracellular aspartate activates the ionotropic N-methyl-d-aspartate receptor in cancer cells, which promotes CREB-dependent expression of deoxyhypusine hydroxylase (DOHH). DOHH is essential for hypusination, a post-translational modification that is required for the activity of the non-classical translation initiation factor eIF5A. In turn, a translational programme with TGFβ signalling as a central hub promotes collagen synthesis in lung-disseminated breast cancer cells. We detected key proteins of this mechanism in lung metastases from patients with breast cancer. In summary, we found that aspartate, a classical biosynthesis metabolite, functions in the lung environment as an extracellular signalling molecule to promote aggressiveness of metastases."

Cancer's frequent spread to the lungs is driven by important amino acid

Researchers reveal why the lung is a frequent site of cancer metastasis (original news release)

Aspartate signalling drives lung metastasis via alternative translation (no pubic access)