Genetic and metabolic comparison of orthotopic and heterotopic patient-derived pancreatic-cancer xenografts to the original patient tumors.

Seung-Mo Hong,Moon-Bo Kim,Soyeon An,Hyun Ju Yoo,In Kyong Shim,Eunsung Jun,Robert M Hoffman,Ji Sun Won,Suhwan Chang,Song Cheol Kim

doi:10.18632/oncotarget.23567

Abstract

Tumors from 25 patients with pancreatic cancer were used to establish two patient-derived xenograft (PDX) models: orthotopic PDX (PDOX) and heterotopic (subcutaneous) PDX (PDHX). We compared gene expression by immunohistochemistry, single-nucleotide polymorphism (SNP), DNA methylation, and metabolite levels. The 4 cases, of the total of 13 in which simultaneous PDHX & PDOX models were established, were randomly selected. The molecular-genetic characteristics of the patient's tumor were well maintained in the two PDX models. SNP analysis demonstrated that both groups were more than 90% identical to the original patient's tumor, and there was little difference between the two models. DNA methylation of most genes was similar among the two models and the original patients tumor, but some gene sets were hypermethylated the in PDOX model and hypomethylated in the PDHX model. Most of the metabolites had a similar pattern to those of the original patient tumor in both PDX tumor models, but some metabolites were more prominent in the PDOX and PDHX models. This is the first simultaneous molecular-genetic and metabolite comparison of patient tumors and their tumors established in PDOX and PDHX models. The results indicate high fidelity of these critical properties of the patient tumors in the two models.

Highlights

DNA methylation of most genes was similar among the two models and the original patients tumor, but some gene sets were hypermethylated the in patient-derived orthotopic xenograft (PDOX) model and hypomethylated in the patient-derived heterotopic xenograft (PDHX) model
Most of the metabolites had a similar pattern to those of the original patient tumor in both patient-derived xenograft (PDX) tumor models, but some metabolites were more prominent in the PDOX and PDHX models
Multivariate analysis showed that tumor size of more than 3.5 cm in the patient was a significant factor related to successful PDX engraftment

Summary

Introduction

Patient-derived xenografts (PDX) models of cancer have demonstrated important utility for the study of the mechanism of cancer, novel drug discovery and evaluation and personalized, precision medicine [1, 2].There are two major types of PDX models: the orthotopic model, termed patient-derived orthotopic xenograft (PDOX) and a heterotopic model with www.impactjournals.com/oncotarget subcutaneous implantation termed patient-derived heterotopic xenograft (PDHX).Toward the goal of precision, personalized oncology, our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) nude mouse model with the technique of surgical orthotopic implantation (SOI), including pancreatic [3,4,5,6,7,8], breast [8], ovarian [9], lung [10], cervical [11, 12], colon [13,14,15], stomach [16], sarcoma [17,18,19,20,21,22,23,24,25,26,27,28] and melanoma [29,30,31,32,33].Our laboratories have focused on patient-derived mouse models of pancreatic cancer [3,4,5,6,7,8].To effectively use pancreatic cancer patientderived xenograft (PDX) models in translational research, successful PDX engraftment of surgical specimens in immune-deficient mice is needed. Toward the goal of precision, personalized oncology, our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) nude mouse model with the technique of surgical orthotopic implantation (SOI), including pancreatic [3,4,5,6,7,8], breast [8], ovarian [9], lung [10], cervical [11, 12], colon [13,14,15], stomach [16], sarcoma [17,18,19,20,21,22,23,24,25,26,27,28] and melanoma [29,30,31,32,33]. There was no correlation of engraftment with surgical procedure, time needed to remove the specimen, tumor differentiation, lymph node metastasis, and protein expression of p53, receptor tyrosine-protein kinase erbB-2 (C-erbB-2), or deleted in pancreatic carcinoma locus 4 (DPC4) [34]

Methods

Results

Conclusion