Assistant Professor of Pathology and
Adjunct Assistant Professor ofOncological Sciences
B.S. University of Iowa
M.D., Ph.D. Washington University School of Medicine
Kimberley Evason's Lab Page
Kimberley Evason's PubMed Literature Search
Molecular Biology Program
Liver, Cancer, Zebrafish, WNT/β-catenin
Liver cancer (hepatocellular carcinoma, (HCC)) is the third leading cause of cancer-related death worldwide. 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 simple care requirements 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. Our ongoing research focuses on two main areas:
- 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.
- Investigating conserved genetic mechanisms of β-catenin-mediated liver tumorigenesis. Genes and pathways that are significantly altered in β-catenin-induced zebrafish liver tumors and in human HCC with activating mutations in β-catenin may play a conserved role in liver tumorigenesis. Through RNA-seq analysis, we have identified genes with increased expression in zebrafish liver tumors induced by activated β-catenin. Many of these genes are also enriched in human HCC. We plan to use gain- and loss-of-function approaches in zebrafish and human HCC cell lines to test the hypothesis that such conserved genes influence liver tumor formation.
- Evason, K.J., Francisco, M.T., Juric, V., Balakrishnan, S., Lopez Pazmino, M. del P., Gordan, J.D., Kakar, S., Spitsbergen, J., Goga, A. and Stainier, D.Y. Identification of Chemical Inhibitors of β-Catenin-Driven Liver Tumorigenesis in Zebrafish. PLoS Genet. 11(7):e1005305. doi: 10.1371/journal.pgen.1005305. eCollection 2015 Jul.
- *Yin, C., *Evason, K.J., Asahina, K., Stainier, D.Y. Hepatic stellate cells in liver development, regeneration, and cancer. J Clin Invest. 23(5):1902-10. *Equal contributions.
- Evason, K.J., Grenert, J.P., Ferrell, L.D., Kakar, S. Atypical hepatocellular adenoma-like neoplasms with β-catenin activation show cytogenetic alterations similar to well-differentiated hepatocellular carcinomas. Hum Pathol. 44(5):750-8.
- *Yin, C., *Evason, K.J., Maher, J.J., Stainier, D.Y. The bHLH transcription factor Hand2 marks hepatic stellate cells in zebrafish: Analysis of stellate cell entry into the developing liver. Hepatology 56(5):1958-70. *Equal contributions.