Development of a Human-Derived Liver Progenitor Cell Line with DNAJB1-PRKACA Fusion Gene 2019 – 2020
Principal Investigator: Khashayar Vakili, MD, Surgical Director of Liver, Kidney, Intestine, and Multivisceral Transplant Programs, Assistant Professor of Surgery, Harvard Medical School
Developing models to study the mechanism by which the DNAJB1-PRKACA fusion protein causes fibrolamellar hepatocellular carcinoma (FLC) is crucial for finding a cure for this cancer. In our lab, we have engineered a kidney cell line (HEK-DP) which contains the DNAJB1-PRKACA fusion gene. This cell line has demonstrated some interesting similarities to FLC tumors and has served as a platform for developing a better understanding of the actions of the fusion protein in the cellular environment.
In this project, we will apply the same strategy that we used to engineer the HEK-DP model to engineer normal human liver progenitor cells to express the DNAJB1-PRKACA fusion gene. This will provide us with a novel model to understand how the fusion protein reprograms the liver progenitor cells into becoming cancerous. Using cells derived from human livers, we have established three-dimensional “organoid” cultures which contain special precursor cells or stem cells. After introducing the fusion gene into these progenitor cells, we will examine changes induced in response to the presence of the fusion protein. Understanding the mechanisms involved in reprogramming of the cells by the fusion protein will give us insights into how to therapeutically target FLHCC.