DnaJ-PKAc fusion induces liver inflammation in a zebrafish model of fibrolamellar carcinoma
ABSTRACT Fibrolamellar carcinoma (FLC) is a rare liver cancer that affects adolescents and young adults. Genomic analysis of FLC has revealed a 400 kb deletion in chromosome 19 that leads to the chimeric transcript DNAJB1-PRKACA (DnaJ-PKAc), comprised of the first exon of heat shock protein 40 (DNAJB1) and exons 2-10 of the catalytic subunit of protein kinase A (PRKACA). Here, we report a new zebrafish model of FLC induced by ectopic expression of zebrafish Dnaja-Pkaca (zfDnaJa-Pkaca) in hepatocytes that is amenable to live imaging of early innate immune inflammation. Expression of zfDnaJa-Pkaca in hepatocytes induces hepatomegaly and increased hepatocyte size. In addition, FLC larvae exhibit early innate immune inflammation characterized by early infiltration of neutrophils and macrophages into the liver microenvironment. Increased Caspase-a (the zebrafish homolog for human caspase-1) activity was also found in the liver of FLC larvae, and pharmacological inhibition of Tnfα and caspase-a decreased liver size and inflammation. Overall, these findings show that innate immune inflammation is an early feature in a zebrafish model of FLC and that pharmacological inhibition of TNFα or caspase-1 activity might be targets to treat inflammation and progression in FLC patients. This article has an associated First Person interview with the first author of the paper. Summary: Inflammation and Caspase-a activation occur early in a new zebrafish model for fibrolamellar carcinoma (FLC). Pharmacological inhibition of TNFα secretion and caspase-1 might be useful approaches to treat FLC patients.