A team of researchers from the University of Rochester discovered how certain genetic mutations fuel the growth of cholangiocarcinoma, a rare but aggressive type of malignancy that has been on the rise in the United States. Their work, published by Guo et al in Cell Reports this week, details the cooperation of two known cancer genes, ARID1A and KRAS, and how they disable tumor suppressor activity.
When both genes are mutated—particularly ARID1A—the pathways that usually shut down tumor activity cannot perform.
The goal is to use the data to find drugs that could restore the normal function of a mutated ARID1A to stop cancer’s growth. The preclinical investigation is specific to cholangiocarcinoma.
Senior study author Aram Hezel, MD, John and Ethel Heselden Professor at the University of Rochester Medical Center and Chief of Hematology/Oncology at Wilmot Cancer Institute, has been pursuing this line of research for 12 years. Dr. Hezel noted that the ARID1A gene, which controls how DNA is organized, can have a different impact on other tissues, cells, and circumstances. But when it loses its normal function in the bile duct cells of the liver, the result is an out-of-control cell cycle. Further, when bile duct cells coincidentally harbor the cancer gene KRAS, cooperation between ARID1A and KRAS may lead to the development of cholangiocarcinoma, data show.
The study authors concluded, “We thus identify an ARID1A-TGF-β-Smad4 axis as essential in limiting the biliary epithelial response to oncogenic insults, while its loss leads to biliary preneoplasia and cholangiocarcinoma.”
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