Within mitochondria, specialized proteins work together to produce energy. Most eukaryotic cells live off of this energy–including cancerous cells, researchers have now found. In a June 29 study published in Nature, a team of scientists concludes that head and neck cancer cells fuel their journey to colonize new locations throughout the body with energy derived from modifying a key mitochondrial protein called NSUN3. The researchers say that NSUN3 is critical for generating energy in the mitochondria and that the protein’s absence confines cancerous cells to their primary tumors.
Before now, cancer cells were known to develop with the energy produced through glycolysis, despite the fact that glycolysis is an inefficient way of making energy. In this study, the researchers found that cells in a primary tumor only tilt toward glycolysis as a backup when there is a shortage of NSUN3 protein in the mitochondria, and that doing so inhibits metastasis.
When postdoctoral researcher Sylvain Delauney arrived at the German Cancer Research Center five years ago, he teamed up with other researchers at the lab of Michaela Frye to investigate the link between NSUN3 and oral cancer. First, the researchers sequenced mitochondrial encoded tRNAs to identify modifications that aid the production of energy. They discovered that the tRNA m5C and its derivative f5C exhibited the highest level of modification in both normal and cancer cells compared to other modifiers.
tRNA modifications aid protein synthesis in the mitochondria and, since NSUN3 facilitates the formation of m5C and f5C, its absence directly affected both modifications, resulting in reduced energy production. Knowing this, Delaunay and his team set out to investigate what happens in the mitochondria in the absence of m5C and f5C modifications.
The researchers depleted the protein NSUN3 from four human oral carcinoma cell lines and injected them into mice. They found that the “appearance of cancer and its growth was completely fine, regardless of the presence of NSUN3. The size of the tumor was the same,” Delaunay tells The Scientist. “But once we looked at the metastasis, we could see that there was much less metastasis if NSUN3 was inactivated. And so we started to dig into this.”
It was when the team quantified the number of tumors expressing or lacking NSUN3, then measured the permeability of the mitochondria’s membranes to metastasis-initiating cells in oral carcinoma that the link between NSUN3 and oral cancer materialized. The researchers found that the removal of NSUN3 from the mitochondria cut the quantity of metastasis-initiating cells by two-thirds. “We finally found that by deleting NSUN3 we could prevent metastasis development by shutting down the production of energy coming from the mitochondria,” says Delaunay.
“That’s something that is fairly new that usually, you don’t see unless you go that deep into checking for evidence at that level,” says Marcos Lopez, a professor of chemistry at the University of Puerto Rico who researches the role of mitochondria in cancer but was not involved in the study.
Delaunay says that the knowledge of how head and neck cancer metastasize could help in devising the means to confine cancerous cells to primary tumors and thus make them more treatable. “Understanding better how the whole mechanism works is very important, because then we can target some things to contain the primary tumor and keep it in the primary site to avoid dissemination,” he says. He and his team began exploring this in the current study, having repurposed an antibiotic that is already on the market to prevent metastasis in mice by suppressing the generation of energy in the mitochondria.
See “New Understanding of Metastasis Could Lead to Better Treatments”
Lopez describes the study as a “game-changer” that could lead to “a new target for treatment to prevent metastasis.” But it’s not yet clear if the finding will apply to other types of cancer, he adds: “Metabolically, all the other types of cancer have their own thing, so we need to see if this metabolic plasticity that they are showing in these types of cancer translates to other types of cancer.”
Correction (July 11): This article previously stated that glycolysis was thought to fuel the growth and spread of cancer, which was inaccurate. It also originally misstated from where the researchers acquired some of their human oral carcinoma cell lines. The Scientist regrets the errors.