Hepatocellular carcinoma (HCC) is the second most common type of primary liver cancer in children with poor prognosis. It consists of fibrolamellar carcinoma (FLC) and non-FLC HCC. Unlike HCC in adult patients, childhood HCC can occur without underlying liver disease/cirrhosis. The research objective of our laboratory is to identify cellular and molecular mechanisms underlying childhood liver cancer development. We are approaching this topic from multiple angles, including alterations in the gene expression and microRNA profiles, abnormal activation of developmental pathways, and metabolic rewiring. We are using in vitro and in vivo models as well as analyses of clinical specimens to test our hypotheses (Figure 1).

Postnatal hepatic progenitor cells are derived from normal hepatic cells activated in response to injury and form ductular reactions. Although ductular reactions are observed in many types of liver disease, the role of hepatic progenitor cells in disease progression remains largely unclear. To investigate the hypothesis that hepatic progenitor cells promote the progression of chronic liver disease in a paracrine manner, we are using genetic mouse models for specific labeling of the progenitor lineage and conditional modulation of signaling pathways in progenitor cells.