Unassuming enzyme adds fuel to the fire in liposarcoma

Cancer-causing genes, called oncogenes, begin as a spark, able to ignite flammable tinder in their vicinity. This oncogene spark causes a shift in some protein function and then combines with a cast of other misbehaving genes, fueling this shift. This cascade of events escalates a spark into the wildfire of cancer as the rogue genes cooperate to steer cells toward rapid growth. 

With a wildfire, containment and future prevention involves finding the initial spark and understanding the layout of the tinder. The same is true for cancer, but such investigations can have surprising outcomes, demonstrating a complexity that needs to be carefully unraveled.

“We’ve learned so much about cancer by studying mutations that involve individual oncogenes and tumor suppressors in cancer,” said Alejandro Gutierrez, MD, St. Jude Department of Oncology. “But it turns out that large DNA copy number variations are exceedingly common in human cancer, and we don’t really understand which genes are the key factors. We think there’s largely unexplored space here to learn about new biology and therapeutic targets.” Gutierrez’s work focuses on separating the sparks from the tinder and outlining the interplay between the two in cancer.

Sarcomas are cancers of the body’s connective tissues: bones, muscles, tendons, etc. Liposarcoma is the most common soft tissue sarcoma type and develops in fatty tissue. Gutierrez has previously uncovered various sparks at the root of the disease, including AKT, a protein kinase responsible for regulating cell metabolism and growth, for which overactivation is one of the most common triggering events in cancer.

In a recent publication in Molecular Cell, Gutierrez and his team continued their exploration of liposarcoma. While exploring the tinder underlying AKT-driven liposarcoma in one particularly flammable patch of the genome, the team noticed something strange. “We identified some new oncogenes, including some that were long suspected. But also, one that was particularly surprising to us,” Gutierrez explained. “METTL1.” 

METTL1 linked to cancer through tRNA side gig

METTL1 is an enzyme involved in translation, a key process in creating proteins from genomic instructions. Within ribosomes, where translation takes place, transfer RNA (tRNA) acts as an amino acid courier, delivering amino acid building blocks one at a time onto a growing chain to eventually form a protein. Translation has many moving parts to it, with METTL1 playing a support role by modifying the tRNA courier to ensure correct positioning within the ribosome. 

Linking METTL1 overexpression to AKT-driven liposarcoma did not make sense to Gutierrez. The enzyme has been linked to cancer through its typical function: modifying tRNA. However, AKT was known to inactivate METTL1, shutting off its function. This ran counterproductive to its apparent role as an exacerbator. It was as if quenching the fire was causing it to spread. 

So, what was METTL1 hiding?

The researchers first ensured the effect they observed wasn’t related to the enzyme’s main function, demonstrating that inactivating this function of METTL1 does not stop the ability of cells to become cancerous. They knew METTL1 had to play a role in another chain of events disrupted by mutation. 

Backtracking along the tinder brought Gutierrez’s team to the source of METTL1’s oncogenic ability: tRNA. Because tRNA acts as a courier, once it has delivered its amino acid cargo, it needs to be “reloaded” at a depot. This depot is called the multi-tRNA synthetase complex (MSC) and is responsible for reloading tRNA with another amino acid, a process called aminoacylation. 

When they removed METTL1, the researchers found that aminoacylation rates dropped, indicating that METTL1 had a secondary role at the MSC depot — but only in cancer cells. The demands of proliferation and multiplication strain the translation process since it must move faster. Cancer cells push METTL1 to the MSC depot to address the new bottleneck of tRNA aminoacylation.

Therapeutic opportunity found within oncogene tinder

This finding exemplified the interconnectivity of oncogenes. “There are many genes on these DNA segments which have a high frequency for variations and are important for cancer formation,” Gutierrez said. “There are some that we found which were previously suspected, and many which interact together in very complicated ways, as we saw with AKT and METTL1.”

Gutierrez sees these complexities as opportunities, however. By identifying the tinder that is most at risk for fire, preventative measures can be taken. In this case, he is exploring therapeutic options for liposarcoma based on METTL1’s new obligate side gig.

“Our work showed that METTL1 promotes tumor growth by increasing protein synthesis, which happens in ribosomes,” Gutierrez explained. “We hypothesized that METTL1-driven tumors might be hypersensitive to inhibiting ribosome formation, which can be achieved with a clinical drug called actinomycin D.” 

The researchers found that low doses of the drug were highly effective at eliminating liposarcoma cells.

The network of cause and effect exemplified by AKT and METTL1 in liposarcoma is a clear indication of the precarious balancing act between benign tinder and igniting spark. However, therein lies opportunity. Finding the reason a fire spreads is the key to preventing future fires. METTL1-based therapies may represent a highly effective future therapeutic route for liposarcoma.

“To gain biological insight into the regulation of proteins, synthesis in normal cells and tumor cells is very important,” Gutierrez said. “And of course, getting real clinical therapy out of this effort is a really exciting opportunity.”