Abstract
ABSTRACTFibrolamellar 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.
Highlights
Fibrolamellar Carcinoma (FLC) is a rare and understudied liver cancer that primarily affects adolescents and young adults
To determine if the fusion transcript drives mass formation in zebrafish, we generated a fusion of the zebrafish dnajb1 and prkaca
We found that the presence of pro-inflammatory macrophages in the liver microenvironment at early stages of progression in HCC larvae is associated with increased tumorigenesis in a model of non-alcoholic fatty liver disease-associated HCC (NAFLD-associated HCC)
Summary
Fibrolamellar Carcinoma (FLC) is a rare and understudied liver cancer that primarily affects adolescents and young adults. Surgery (resection/liver transplantation) is the most common treatment for FLC patients. Recurrence is very common in FLC patients and the therapeutic options are not very effective. Studies have focused on identifying the molecular mechanisms that drive the disease {Dhingra, 2010 #1686;Li, 2010 #1698;Ross, 2011 #1658;Simon, 2015 #1640;Honeyman, 2014 #1623;Oikawa, 2015 #1624;Graham, 2015 #3081;Dinh, 2019 #4387;Dinh, 2017 #3076;Riehle, 2019 #4404;Riggle, 2016 #1639}{Turnham, 2019 #4384}. There is only one unique molecular target responsible for driving the disease, the DNAJB1-PRKACA fusion transcript that results from a 400kb deletion on chromosome 19 (Cornella et al, 2015; Dinh et al, 2017; Honeyman et al, 2014; Simon et al, 2015). Recently developed murine models using CRISPR/Cas or overexpression of this fusion transcript have shown that DNAJB1-PRKACA is sufficient to drive tumorigenesis in vivo (Engelholm et al, 2017; Kastenhuber et al, 2017)
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