. Scientific Frontline: A New Cancer Mechanism: Failed Cell Housekeeping

Tuesday, May 9, 2023

A New Cancer Mechanism: Failed Cell Housekeeping

Illustration of single-stranded RNA
Illustration Credit: National Institute of General Medical Sciences

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 in the journal 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 percent 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.”

Funding: This work was funded by the Damon Runyon Cancer Foundation, American Society of Clinical Oncology, National Institutes of Health (grants T32HL116324, T32GM135134, R35GM144283, P01CA042063, R01GM034277, R01CA133404, R01CA103846, R01GM141544, K08CA248727, and an Intramural Research Program (IRP) of the Division of Cancer Epidemiology and Genetics grant), Charles S. Memorial Sloan Kettering Starr Foundation Cancer Consortium, Hope Funds for Cancer Research Grillo-Marxuach Family Fellowship, American Lebanese Syrian Associated Charities, University of Rochester Health Sciences Center, David H. Koch Foundation, Ludwig Center at Harvard, and Deutsche Forschungsgemeinschaft under Germany’s Excellence Strategy (EXC2151–390873048 and grant GE 976/9-2).

Published in journalScience

Additional authors: Brian Abraham, Sara Dubbury, Ines Kaltheuner, Sofia Dust, Constance Wu, Kevin Chen, David Liu, Stanislav Bellaousov, Anna Cox, Benjamin Martin, Tongwu Zhang, Calvin Ludwig, Tania Fabo, Rodsy Modhurima, Dakarai Esgdaille, Telmo Henriques, Kevin Brown, Stephen Chanock, Matthias Geyer, Karen Adelman, Phillip Sharp, Richard Young, and Paul Boutz.

Source/CreditHarvard Medical School | Nancy Fliesler

Reference Number: med050923_01

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