Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Tragically, the majority of patients with HCC present with disease that is too advanced to benefit from potentially curative treatments such as surgical resection or ablation.  

The overarching goal of the Evason laboratory is to investigate mechanisms involved in liver tumorigenesis in order to develop improved therapies to treat this deadly cancer. A major subset of HCC is defined by mutations in the CTNNB1 gene encoding β-catenin, an integral component of the Wnt signaling pathway. These β-catenin-activated HCC represent 20-40% of human HCC, and our current research focuses primarily on these tumors.

The search for targeted HCC treatments has been hampered by the lack of relevant animal models for the genetically diverse subsets of HCC. To address this chemotherapeutic challenge, we have created and characterized transgenic zebrafish models to use as experimental tools. Zebrafish represents an excellent model system for studies of human cancer, given the powerful genetics, large brood size, and facile husbandry of this vertebrate animal. Importantly, zebrafish develop tumors that are histologically and genetically similar to human cancers. Chemical screens can be easily conducted on embryos or larvae, enabling large-scale testing of possible chemotherapeutic agents. The resources available at the University of Utah and the Huntsman Cancer Institute, including centralized zebrafish and imaging facilities, are critical for our experiments.

We found that transgenic zebrafish expressing hepatocyte-specific activated β-catenin develop HCC. Using this novel transgenic model, we screened for druggable pathways that mediate β-catenin-induced liver growth and identified two c-Jun N-terminal kinase (JNK) inhibitors and two serotonergic antidepressants that suppressed this phenotype.  One of these antidepressants, amitriptyline, decreased liver tumor burden in a mouse HCC model.  Our studies implicate JNK inhibitors and antidepressants as potential therapeutics for β-catenin-induced liver tumors. Some current areas of ongoing research include:

1. Characterizing chemical compounds, including amitriptyline, that inhibit β-catenin-induced liver growth and tumor formation.  The JNK pathway has a well-established role in liver tumorigenesis, supporting the effectiveness of our chemical screening approach in identifying mechanisms involved in hepatocarcinogenesis.  On the other hand, it is less clear how our other class of hits, serotonergic antidepressants, are inhibiting β-catenin mediated liver enlargement and tumorigenesis.  What are the mechanisms by which amitriptyline might inhibit liver tumor formation?  What is the role of serotonin and related neurotransmitters in liver tumorigenesis?  In addition to JNK inhibitors and antidepressants, we have identified a handful of other hit drugs that suggest additional pathways to explore experimentally.
2. Defining how dysregulated lipid metabolism and inflammation influences hepatocarcinogenesis. The incidence of HCC is increasing in parallel with the obesity epidemic and accompanying disorders including metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD). MASLD is characterized by abnormal accumulation of lipids (fat), inflammation, and progressive fibrosis that culminate in cirrhosis, a major risk factor for HCC. We and others have found that HCC tumors themselves have aberrant fat metabolism. Projects in the Evason lab include: 1) identifying and characterizing microRNAs that drive dysregulated lipid metabolism and inflammation in HCC; 2) identifying and characterizing lipid metabolic changes in HCC.
3. Liver development. Many of the molecular pathways and cellular behaviors that govern development are co-opted by tumors to drive growth, de-differentiation, and metastasis. Hepatic stellate cells are mesenchymal, non-hepatocyte liver cells that produce extracellular matrix and are the main cell type responsible for fibrosis during MASLD and other chronic liver diseases. The Evason lab studies molecular pathways that influence hepatic stellate cell development. 

References

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