A novel patient-derived orthotopic xenograft model of esophageal adenocarcinoma provides a platform for translational discoveries

Abstract

Mouse models of gastroesophageal junction (GEJ) cancer strive to recapitulate the intratumoral heterogeneity and cellular crosstalk within patient tumors to improve clinical translation. GEJ cancers remain a therapeutic challenge due to the lack of a reliable mouse model for preclinical drug testing. In this study, a novel patient-derived orthotopic xenograft (PDOX) was established from GEJ cancer via transabdominal surgical implantation. Patient tumor was compared to subcutaneously implanted patient-derived tumor xenograft (PDX) and PDOX by Hematoxylin and Eosin staining, immunohistochemistry and next-generation sequencing. Treatment efficacy studies of radiotherapy were performed. We observed that mechanical abrasion of mouse GEJ prior to surgical implantation of a patient-derived tumor in situ promotes tumor engraftment (100%, n=6). Complete PDOX engraftment was observed with rapid intra- and extraluminal tumor growth, as evidenced by magnetic resonance imaging. PDOXs contain fibroblasts, tumor-associated macrophages, immune and inflammatory cells, vascular and lymphatic vessels. Stromal hallmarks of aggressive GEJ cancers are recapitulated in a GEJ PDOX mouse model. PDOXs demonstrate tumor invasion into vasculature and perineural space. Next-generation sequencing revealed loss of heterozygosity with very high allelic frequency in NOTCH3, TGFB1, EZH2 and KMT2C in the patient tumor, the subcutaneous PDX and the PDOX. Immunohistochemical analysis of Her2/neu (also known as ERBB2), p53 (also known as TP53) and p16 (also known as CDKN2A) in PDX and PDOX revealed maintenance of expression of proteins found in patient tumors, but membranous EGFR overexpression in patient tumor cells was absent in both xenografts. Targeted radiotherapy in this model suggested a decrease in size by 61% according to Response Evaluation Criteria in Solid Tumors (RECIST), indicating a partial response to radiation therapy. Our GEJ PDOX model exhibits remarkable fidelity to human disease and captures the precise tissue microenvironment present within the local GEJ architecture, providing a novel tool for translating findings from studies on human GEJ cancer. This model can be applied to study metastatic progression and to develop novel therapeutic approaches for the treatment of GEJ cancer.This article has an associated First Person interview with the first author of the paper.

PDX models of human lung squamous cell carcinoma: consideration of factors in preclinical and co-clinical applications

“…To improve the success rate of initial engraftment, the authors might as well consider a slightly different approach such as the use of orthotopic PDX models [37] presumably because the low success rate of initial tumor engraftment could be caused by the heterotopic interactions of the tumor samples from the patients with the mouse subcutaneous environment, not by the patients' clinical parameters as shown in Table 1. And to lower the XALD incidence, rituximab treatment to the tumor fragments from the patients prior to xenotransplantation could be employed [35,36].…”

Development of Prognostic Signature Based on Pan-cancer Proteomics

“…Since metabolic reprogramming was a well-established hallmark of cancer, alterations in metabolism-related proteins expression were common in tumors. 24 According to the Figure 4, metabolically related DEPs were roughly divided into two groups: carbohydrate metabolism-related proteins and amino acid metabolism-related proteins. ENO3, FBP1, FBP2, GPD1, and ALDOB were all glycolytic pathway related proteins with inhibitory effects on tumor.…”

Patient-derived xenograft: a developing tool for screening biomarkers and potential therapeutic targets for human esophageal cancers

“…In Table 2 , the success rates of PDX for other tumors including neuroblastoma, osteosarcoma, osteosarcoma and so on are listed, which vary from 24% to 100%. The take rate of orthotopic PDX for EC is claimed as 100%, however, the extremely limited sample size (only one case) used in this study may strongly affect the estimation of the take rate [ 15 ]. Because of the anatomical location of the esophagus, the establishment of orthotopic model of EC requires advanced surgical techniques, and hardly achieves simplicity or reproducibility [ 16 , 17 ].…”

“…Orthotopic implantation of human primary EC tissues is scarcely reported. Veeranki et al [ 15 ] transabdominally implanted a biopsy sample of EAC at the distal esophagus/gastroesophageal junction to mimic tumor growth patterns in patients. The orthotopic mouse model closely mimics tumor growth patterns seen in patients and recapitulated the response to radiation treatment in patients with EAC [ 15 ].…”