Min Zhu1, Lin Li1, Tianshi Lu1,2, Hyesun Yoo3,4, Ji Zhu3,4, Purva Gopal5, Sam C Wang6, Matthew R Porembka6, Nicole E Rich7, Sofia Kagan7, Mobolaji Odewole7, Veronica Renteria7, Akbar K Waljee4,8,9, Tao Wang2, Amit G Singal7, Adam C Yopp6, Hao Zhu1. 1. Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX. 2. Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX. 3. Department of Statistics, University of Michigan, Ann Arbor, MI. 4. Michigan Integrated Center for Health Analytics and Medical Prediction, Ann Arbor, MI. 5. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX. 6. Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX. 7. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX. 8. VA Center for Clinical Management Research, VA Ann Arbor Health Care System, Ann Arbor, MI. 9. Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine and Michigan Integrated Center for Health Analytics and Medical Prediction, Ann Arbor, MI.
Abstract
BACKGROUND AND AIMS: Several major factors limit our understanding of hepatocellular carcinoma (HCC). First, human HCCs are infrequently biopsied for diagnosis and thus are not often biologically interrogated. Second, HCC initiation and progression are strongly influenced by the cirrhotic microenvironment, and the exact contributions of intrinsic and extrinsic tumor factors are unclear. A powerful approach to examine the personalized biology of liver cancers and the influence of host tissues is with patient-derived xenograft (PDX) models. In Asia, HCCs from patients with hepatitis B virus have been efficiently converted into PDXs, but few parallel efforts from the west have been reported. APPROACH AND RESULTS: In a large-scale analysis, we implanted 93 HCCs and 8 cholangiocarcinomas (CCAs) to systematically analyze host factors and to define an optimized platform for PDX development from both surgical and biopsy samples. NOD Scid IL-2Rγ-/- (NSG) mice that had undergone partial hepatectomy (PHx) represented the best combination of engraftability, growth, and passageability, but overall rates were low and indicative of a unique intrinsic biology for HCCs in the United States. PDX models preserved the histology and genetic features of parental tumors, and ultimately, eight models were usable for preclinical studies. Intriguingly, HCC PDXs were differentially sensitive to regorafenib and sorafenib, and CCA PDXs were also highly sensitive to regorafenib. CONCLUSIONS: PDX models functionalize early and advanced stage HCCs and revealed unique biological features of liver cancers from the United States.
BACKGROUND AND AIMS: Several major factors limit our understanding of hepatocellular carcinoma (HCC). First, humanHCCs are infrequently biopsied for diagnosis and thus are not often biologically interrogated. Second, HCC initiation and progression are strongly influenced by the cirrhotic microenvironment, and the exact contributions of intrinsic and extrinsic tumor factors are unclear. A powerful approach to examine the personalized biology of liver cancers and the influence of host tissues is with patient-derived xenograft (PDX) models. In Asia, HCCs from patients with hepatitis B virus have been efficiently converted into PDXs, but few parallel efforts from the west have been reported. APPROACH AND RESULTS: In a large-scale analysis, we implanted 93 HCCs and 8 cholangiocarcinomas (CCAs) to systematically analyze host factors and to define an optimized platform for PDX development from both surgical and biopsy samples. NODScid IL-2Rγ-/- (NSG) mice that had undergone partial hepatectomy (PHx) represented the best combination of engraftability, growth, and passageability, but overall rates were low and indicative of a unique intrinsic biology for HCCs in the United States. PDX models preserved the histology and genetic features of parental tumors, and ultimately, eight models were usable for preclinical studies. Intriguingly, HCC PDXs were differentially sensitive to regorafenib and sorafenib, and CCA PDXs were also highly sensitive to regorafenib. CONCLUSIONS: PDX models functionalize early and advanced stage HCCs and revealed unique biological features of liver cancers from the United States.
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