Deep in the Bile Ducts, Researchers Explore How Cancer Arises

Mar. 12, 2024
Originally published August 31, 2022. Updated March 12, 2024.
Aram Hezel, MD, and his research team discovered another important step in what causes an aggressive type of liver cancer called cholangiocarcinoma. Investigators were studying the relationship between several genes and liver injury (gall stones in the bile ducts, alcohol abuse, and infection, for example), and one gene, SMAD4, stood out. It plays a unique and major role in suppressing the overgrowth of liver cells and tumors. But when SMAD4 is inactivated, it can no longer stop cancer from developing, researchers discovered in mice. Investigating this further could help doctors diagnose cholangiocarcinoma earlier and help researchers develop effective treatments to reduce the devastating impact of this rare cancer. The study was reported in the journal, Disease Models & Mechanisms, and was funded by the National Institutes of Health, the National Cancer Institute, and the For Pete’s Sake Golf Tournament in memory of Pete Osterling.

A Wilmot Cancer Institute scientist discovered how gene mutations fuel the growth of bile duct cancer, a rare but aggressive type of liver cancer that has been on the rise in the U.S.

Aram Hezel, M.D., published the work in Cell Reports this week. The paper is significant because it 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 pre-clinical investigation is specific to cholangiocarcinoma, also known as bile duct cancer, which is the second most common type of liver cancer.

Hezel has been pursuing this line of research for 12 years. He is the John and Ethel Heselden professor the University of Rochester Medical Center and chief of Hematology/Oncology at Wilmot.

Aram Hezel headshot 2021 2

Liver cancers include both hepatocellular carcinoma or cholangiocarcinoma. They can occur for a variety of reasons including cirrhosis due to alcohol abuse, liver disease due to diabetes or obesity, or viral liver infections.

What is the survival rate for bile duct cancer? Estimates are 25 percent if the disease is caught in early stages, and the survival rate drops to less than 10 percent if the cancer had already begun to spread, according to the American Society of Clinical Oncology.

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 the Arida1a and Kras leads to cholangiocarcinoma, data show.

Bing Guo, Ph.D., a postdoctoral fellow in Hezel’s lab, led much of the bile duct cancer research. He is funded by the Wilmot Cancer Research Fellowship award. The National Institutes of Health also supported the study with grants to Hezel and co-author Hucky Land, Ph.D., deputy director of Wilmot. Laurie Steiner, M.D., associate professor of Pediatrics at URMC, played a significant role in the investigation as did the UR Genomics Research Center led by John Ashton, Ph.D., M.B.A. and the gastro-intestinal pathology team from the Department of Pathology and Laboratory Medicine, including Christa L Whitney-Miller, M.D., vice chair of anatomic pathology; Diana Agostini-Vulaj, D.O., and Aaron R. Huber, D.O.