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.
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The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.
The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.
The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.