Skip to content

Bioscience PhD Programs

Main Navigation

Kimberley Evason

Associate Professor of Anatomic Pathology and Adjunct Assistant Professor of Oncological Sciences

Liver, Cancer, Zebrafish, WNT/β-catenin

Evason Photo

 

Molecular Biology Program

Education

B.S. University of Iowa

M.D. Ph.D. Washington University School of Medicine

Links

Lab Page

PubMed Literature Search

kimberley.evason@hci.utah.edu

 

Research

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:

  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 [7], 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. 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.

References

  1. Evason KJ, Swanson EA (2019). Epithelial Inclusions in Gallbladder May Mimic Parasite Infection. Am J Clin Pathol, 152(3), 399-402.
  2. Dubey JP, Evason KJ, Walther Z (2019). Endogenous development of Cystoisospora belli in intestinal and biliary epithelium of humans. Parasitology, 146(7), 865-872.
  3. Chaturantabut S, Shwartz A, Evason KJ, Cox AG, Labella K, Schepers AG, Yang S, Acuña M, Houvras Y, Mancio-Silva L, Romano S, Gorelick DA, Cohen DE, Zon LI, Bhatia SN, North TE, Goessling W (2019). Estrogen Activation of G-Protein-Coupled Estrogen Receptor 1 Regulates Phosphoinositide 3-Kinase and mTOR Signaling to Promote Liver Growth in Zebrafish and Proliferation of Human Hepatocytes. Gastroenterology, 156(6), 1788-1804.e13.
  4. Runtsch MC, Nelson MC, Lee SH, Voth W, Alexander M, Hu R, Wallace J, Petersen C, Panic V, Villanueva CJ, Evason KJ, Bauer KM, Mosbruger T, Boudina S, Bronner M, Round JL, Drummond MJ, O'Connell RM (2019). Anti-inflammatory microRNA-146a protects mice from diet-induced metabolic disease. PLoS Genet, 15(2), e1007970.
  5. Swanson EA, March JK, Clayton F, Couturier MR, Arcega R, Smith R, Evason KJ (2018). Epithelial Inclusions in Gallbladder Specimens Mimic Parasite Infection: Histologic and Molecular Examination of Reported Cystoisospora belli Infection in Gallbladders of Immunocompetent Patients. Am J Surg Pathol, 42(10), 1346-1352.
  6. So J, Khaliq M, Evason K, Ninov N, Martin BL, Stainier DYR, Shin D. (4/19/2018). Wnt/β-catenin signaling controls intrahepatic biliary network formation in zebrafish by regulating Notch activity. Hepatology.
  7. Anderton B, Camarda R, Balakrishnan S, Balakrishnan A, Kohnz RA, Lim L, Evason KJ, Momcilovic O, Kruttwig K, Huang Q, Xu G, Nomura DK, Goga A (2017). MYC-driven inhibition of the glutamate-cysteine ligase promotes glutathione depletion in liver cancer. EMBO Rep, 18(4), 569-585.
  8. Fernandes MA, Braun HJ, Evason K, Rhee S, Perito ER. (2016). De novo inflammatory bowel disease after pediatric kidney or liver transplant. Pediatr Transplant, 21(1).
  9. Cox AG, Tsomides A, Kim AJ, Saunders D, Hwang KL, Evason KJ, Heidel J, Brown KK, Yuan M, Lien EC, Lee BC, Nissim S, Dickinson B, Chhangawala S, Chang CJ, Asara JM, Houvras Y, Gladyshev VN, Goessling W (2016). Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis. Proc Natl Acad Sci U S A, 113(38), E5562-71.
  10. Cox AG, Hwang KL, Brown KK, Evason K, Beltz S, Tsomides A, O'Connor K, Galli GG, Yimlamai D, Chhangawala S, Yuan M, Lien EC, Wucherpfennig J, Nissim S, Minami A, Cohen DE, Camargo FD, Asara JM, Houvras Y, Stainier DYR, Goessling W (2016). Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth. Nat Cell Biol, 18(8), 886-896.
  11. Juric V, Ruffell B, Evason KJ, Hu J, Che L, Wang L, Chen X, Bishop JM (2016). Monocytes promote liver carcinogenesis in an oncogene-specific manner. J Hepatol, 64(4), 881-90.
  12. Evason KJ, Francisco MT, Juric V, Balakrishnan S, Lopez Pazmino Mdel P, Gordan JD, Kakar S, Spitsbergen J, Goga A, Stainier DY (2015). Identification of Chemical Inhibitors of β-Catenin-Driven Liver Tumorigenesis in Zebrafish. PLoS Genet, 11(7), e1005305.
  13. Kelley RK, Magbanua MJ, Butler TM, Collisson EA, Hwang J, Sidiropoulos N, Evason K, McWhirter RM, Hameed B, Wayne EM, Yao FY, Venook AP, Park JW. (2015). Circulating tumor cells in hepatocellular carcinoma: a pilot study of detection, enumeration, and next-generation sequencing in cases and controls. BMC Cancer, 15206.
  14. Huskey NE, Guo T, Evason KJ, Momcilovic O, Pardo D, Creasman KJ, Judson RL, Blelloch R, Oakes SA, Hebrok M, Goga A. (2015). CDK1 inhibition targets the p53-NOXA-MCL1 axis, selectively kills embryonic stem cells, and prevents teratoma formation. Stem Cell Reports, 4(3), 374–389.
  15. Parks AL, McWhirter RM, Evason K, Kelley RK. (2015). Cases of spontaneous tumor regression in hepatobiliary cancers: implications for immunotherapy? J Gastrointest Cancer, 46(2), 161 - 165.
  16. Ghajar CM, Peinado H, Mori H, Matei IR, Evason KJ, Brazier H, Almeida D, Koller A, Hajjar KA, Stainier DY, Chen EI, Lyden D, Bissell MJ (2013). The perivascular niche regulates breast tumour dormancy. Nat Cell Biol, 15(7), 807-17.
  17. Evason KJ, Grenert JP, Ferrell LD, Kakar S (2013). Atypical hepatocellular adenoma-like neoplasms with beta-catenin activation show cytogenetic alterations similar to well-differentiated hepatocellular carcinomas. Hum Pathol, 44(5), 750-8.
  18. Balabaud C, Al-Rabih WR, Chen PJ, Evason K, Ferrell L, Hernandez-Prera JC, Huang SF, Longerich T, Park YN, Quaglia A, Schirmacher P, Sempoux C, Thung SN, Torbenson M, Wee A, Yeh MM, Yeh SH, Le Bail B, Zucman-Rossi J, Bioulac-Sage P (2013). Focal Nodular Hyperplasia and Hepatocellular Adenoma around the World Viewed through the Scope of the Immunopathological Classification. Int J Hepatol, 2013268625.
  19. Yin C, Evason KJ, Maher JJ, Stainier DY (2012). The basic helix-loop-helix transcription factor, heart and neural crest derivatives expressed transcript 2, marks hepatic stellate cells in zebrafish: analysis of stellate cell entry into the developing liver. Hepatology, 56(5), 1958-70.
  20. Cheung ID, Bagnat M, Ma TP, Datta A, Evason K, Moore JC, Lawson ND, Mostov KE, Moens CB, Stainier DY (2012). Regulation of intrahepatic biliary duct morphogenesis by Claudin 15-like b. Dev Biol, 361(1), 68-78.
  21. Evason K, Bove KE, Finegold MJ, Knisely AS, Rhee S, Rosenthal P, Miethke AG, Karpen SJ, Ferrell LD, Kim GE (2011). Morphologic findings in progressive familial intrahepatic cholestasis 2 (PFIC2): correlation with genetic and immunohistochemical studies. Am J Surg Pathol, 35(5), 687-96.
  22. Mirheydar H, Evason K, Coakley F, Baskin LS, DiSandro M. (2009). 46, XY female with cloacal exstrophy and masculinization at puberty. J Pediatr Urol, 5(5), 408–411.
  23. Collins JJ, Evason K, Pickett CL, Schneider DL, Kornfeld K (2008). The anticonvulsant ethosuximide disrupts sensory function to extend C. elegans lifespan. PLoS Genet, 4(10), e1000230.
  24. Evason K, Collins JJ, Huang C, Hughes S, Kornfeld K (2008). Valproic acid extends Caenorhabditis elegans lifespan. Aging Cell, 7(3), 305-17.
  25. Hughes SE, Evason K, Xiong C, Kornfeld K (2007). Genetic and pharmacological factors that influence reproductive aging in nematodes.. PLoS Genet, 3(2), e25.
  26. Evason K, Huang C, Yamben I, Covey DF, Kornfeld K (2005). Anticonvulsant medications extend worm life-span. Science, 307(5707), 258-62.
  27. Morris EJ, Evason K, Wiand C, L'Ecuyer TJ, Fulton AB (2000). Misdirected vimentin messenger RNA alters cell morphology and motility.. J Cell Sci, 113(Pt 13), 2433-43.
Last Updated: 7/12/22