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New cancer mechanism identified: Broken 'vacuum cleaner' in cells

By Nancy Fliesler, Boston Children's Hospital

Cancer can stem from mutations in many different genes.

New research pinpoints a gene that, when mutated, causes cancer through a mechanism scientists haven't seen before: cells lose the ability to dispose of their trash, namely defective strands of RNA.

This mechanism appears to cut across many different malignancies and could present a whole new set of molecules for cancer drugs to target, as reported April 21 in Science by a team from Harvard Medical School, Boston Children's Hospital, and Dana-Farber Cancer Institute.

While studying zebrafish, Megan Insco, HMS instructor in medicine who was a research fellow in the lab of Leonard Zon at HMS and Boston Children's at the time, identified a tumor-suppressing gene called CDK13. When mutated, it expedited the development of melanoma.

The same gene was also mutated in many human melanomas, she found. But what was really surprising was how the CDK13 mutation causes cancer.

Investigating the RNAs made by melanoma cells, Insco saw multiple short, defective RNAs. She immediately shared this odd finding with Zon.

"I said, 'that definitely is interesting,'" recalled Zon, professor of stem cell and regenerative biology at Harvard University and director of the Stem Cell Research Program at Boston Children's. "It took years to figure out what it meant."

A broken vacuum cleaner
It's normal for cells to make a small number of short, defective RNAs. Typically, surveillance machinery in the cell nucleus spots these and disposes of them.

"There are hundreds of steps in making RNAs, and sometimes it doesn't go right," explained Insco, who now runs her own lab at Dana-Farber.

"They're mistakes that are usually discarded. In this case, we found that the cell was not cleaning them up. The vacuum cleaner was broken, so the RNAs were building up."

These "junk" RNA molecules by themselves dramatically accelerated the progression of melanoma. (In her lab, Insco will investigate whether the effect is due to the RNAs themselves or abnormal proteins made from the RNAs.)

Insco further showed that the protein CDK13 is at the center of the cell's RNA surveillance/cleanup system. It modifies a protein called ZC3H14 that in turn recruits a complex of proteins to do the cleanup work. CDK13 functions the same way in zebrafish, mouse, and human cells, she found.

All told, the research suggests that CDK13, or the proteins it regulates, could be targeted to treat multiple cancers.

In melanoma alone, 21% of the human tumors the team examined had mutations in CDK13 or one of the proteins downstream of it.

The team also found mutations in CDK13, ZC3H14, or related proteins in other human tumors, including non-melanoma skin cancer, endometrial cancer, colon adenocarcinoma, and small cell lung cancer.

"There's a cleanup mechanism that isn't working in these cancers," said Zon. "Further defining how RNAs are controlled and processed in cancer will be a major question for developing therapeutics."

Source: Harvard Medical School

Published July 2023

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