Unlocking Aggressive Hepatoblastoma’s Origin Story
Published May 1, 2018 | Hepatology
A recent discovery at Cincinnati Children’s has uncovered the origin of aggressive hepatoblastoma, which has long been a mystery.
Using mouse models and human hepatoblastoma tumor samples, the researchers found that the disease occurs when mature hepatocytes de-differentiate into cancer stem cells.
“These early steps of the disease process are identical to what happens with adult hepatocellular carcinoma, but opposite the classic hepatoblastoma process, in which hepatic stem cells are unable to differentiate into mature hepatocytes, giving rise to liver cancer,” says the study’s lead investigator, Nikolai Timchenko, PhD, whose lab studies the molecular mechanisms of liver cancer.
A month after this research appeared in Hepatology, another study by Timchenko’s lab was published, in the journal Communications Biology. It pointed to the true villain in aggressive hepatoblastoma’s origin story.
Using extensive biological and genetic tests on donated human tumor samples, researchers found highly elevated levels of the protein PARP1. The protein modifies chromatin structure in the cell nucleus to drive the chemotherapy-resistant form of liver cancer.
In their tests on human liver tumor cells, Timchenko and colleagues learned that PARP1 binds to DNA regions within many cancer-related genes and activates their expression in hepatoblastoma to drive the disease. When the researchers used the FDA-approved drug olaparib to block PARP1 in the tumor cells, this slowed or stopped cancer progression.
“These recent discoveries are moving the field a step closer to developing personalized therapies based on the molecular mechanism of aggressive hepatoblastoma,” Timchenko says. “Now, our lab is using patient-derived xenograft cancer models to determine whether PARP1 inhibitors that treat other types of cancer will block the progression of this disease.”
