Development and comprehensive characterization of porcine hepatocellular carcinoma for translational liver cancer investigation

Abstract

// Ron C. Gaba 1 , 2 , Lobna Elkhadragy 1 , F. Edward Boas 3 , Sulalita Chaki 4 , Hanna H. Chen 1 , Mohammed El-Kebir 5 , Kelly D. Garcia 6 , Eileena F. Giurini 1 , Grace Guzman 2 , Francesca V. LoBianco 7 , Mario F. Neto 1 , Jordan L. Newson 1 , Aisha Qazi 4 , Maureen Regan 8 , Lauretta A. Rund 4 , Regina M. Schwind 1 , Matthew C. Stewart 9 , Faith M. Thomas 4 , Herbert E. Whiteley 9 , Jiaqi Wu 5 , Lawrence B. Schook 1 , 4 , 10 and Kyle M. Schachtschneider 1 , 8 , 10 1 Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA 2 Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA 3 Department of Radiology, Memorial Sloan Kettering Cancer Center, New York City, NY, USA 4 Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA 5 Department of Computer Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA 6 Biological Resources Laboratory, University of Illinois at Chicago, Chicago, IL, USA 7 College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA 8 Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA 9 College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA 10 National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, Urbana, IL, USA Correspondence to: Kyle M. Schachtschneider, email: kschach2@uic.edu Keywords: liver cancer; transgenic pigs; large animal model; interventional radiology; personalized medicine Received: April 13, 2020     Accepted: June 01, 2020     Published: July 14, 2020 ABSTRACT Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. New animal models that faithfully recapitulate human HCC phenotypes are required to address unmet clinical needs and advance standard-of-care therapeutics. This study utilized the Oncopig Cancer Model to develop a translational porcine HCC model which can serve as a bridge between murine studies and human clinical practice. Reliable development of Oncopig HCC cell lines was demonstrated through hepatocyte isolation and Cre recombinase exposure across 15 Oncopigs. Oncopig and human HCC cell lines displayed similar cell cycle lengths, alpha-fetoprotein production, arginase-1 staining, chemosusceptibility, and drug metabolizing enzyme expression. The ability of Oncopig HCC cells to consistently produce tumors in vivo was confirmed via subcutaneous (SQ) injection into immunodeficient mice and Oncopigs. Reproducible development of intrahepatic tumors in an alcohol-induced fibrotic microenvironment was achieved via engraftment of SQ tumors into fibrotic Oncopig livers. Whole-genome sequencing demontrated intrahepatic tumor tissue resembled human HCC at the genomic level. Finally, Oncopig HCC cells are amenable to gene editing for development of personalized HCC tumors. This study provides a novel, clinically-relevant porcine HCC model which holds great promise for improving HCC outcomes through testing of novel therapeutic approaches to accelerate and enhance clinical trials.