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TSRI Scientists Discover Mechanism that Turns Mutant Cells into Aggressive Cancers

LA JOLLA, CA – May 26, 2016 – Scientists at The Scripps Research Institute (TSRI) have caught a cancer-causing mutation in the act.

A new study shows how a gene mutation found in several human cancers, including leukemia, gliomas and melanoma, promotes the growth of aggressive tumors.

“We’ve found the mechanism through which this mutation leads to a scrambling of the genome,” said TSRI Associate Professor Eros Lazzerini Denchi, who co-led the study with Agnel Sfeir of New York University (NYU) School of Medicine. “That’s when you get really massive tumors.”

The research, published May 26, 2016 by the journal Cell Reports, also suggests a possible way to kill these kinds of tumors by targeting an important enzyme.

A Puzzling Finding

The researchers investigated mutations in a gene that codes for the protein POT1. This protein normally forms a protective cap around the ends of chromosomes (called telomeres), stopping cell machinery from mistakenly damaging the DNA there and causing harmful mutations.

POT1 is so critical that cells without functional POT1 would rather die than pass on POT1 mutations. Stress in these cells leads to the activation of an enzyme, called ATR, that triggers programmed cell death.

Knowing this, scientists in recent years were surprised to find recurrent mutations affecting POT1 in several human cancers, including leukemia and melanoma.

“Somehow those cells found a way to survive—and thrive,” said Lazzerini Denchi. “We thought that if we could understand how that happens, maybe we could find a way to kill those cells.”

It Takes Two to Tango

Using a mouse model, the researchers found that mutations in POT1 lead to cancer when combined with a mutation in a gene called p53.

“The cells no longer have the mechanism for dying, and mice develop really aggressive thymic lymphomas,” said Lazzerini Denchi.

P53, a well-known tumor suppressor gene, is a cunning accomplice. When mutated, it overrides the protective cell death response initiated by ATR. Then, without POT1 creating a protective cap, the chromosomes are fused together and the DNA is rearranged, driving the accumulation of even more mutations. These mutant cells go on to proliferate and become aggressive tumors.

The findings led the team to consider a new strategy for killing these tumors.

Scientists know that all cells—even cancer cells—will die if they have no ATR. Since tumors with mutant POT1 already have low ATR levels, the researchers think a medicine that knocks out the remaining ATR could kill tumors without affecting healthy cells. “This study shows that by looking at basic biological questions, we can potentially find new ways to treat cancer,” said Lazzerini Denchi.

The researchers plan to investigate this new therapeutic approach in future studies.

In addition to Lazzerini Denchi and Sfeir, authors of the study, “Telomere replication stress induced by POT1 inactivation accelerates tumorigenesis,” were Angela Beal and Nidhi Nair of TSRI; Alexandra M. Pinzaru, Aaron F. Phillips, Eric Ni and Timothy Cardozo of the NYU School of Medicine; Robert A. Hom and Deborah S. Wuttke of the University of Colorado; and Jaehyuk Choi of Northwestern University.

The study was supported by the National Institutes of Health (grants AG038677, CA195767 and GM059414), a NYSTEM institutional training grant (C026880), a scholarship from the California Institute for Regenerative Medicine, a Ruth L. Kirschstein National Research Service Award (GM100532), The V Foundation for Cancer Research, two Pew Stewart Scholars Awards and the Novartis Advanced Discovery Institute.

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.

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Eros Lazzerini Denchi (above) of The Scripps Research Institute co-led the study with Agnel Sfeir of New York University School of Medicine. (High-res image)


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