Abstract
ABSTRACTMouse 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.
Highlights
Since the 1970s, gastroesophageal (GE) cancers are an increasing cause of cancer burden globally (Blot et al, 1991; Fitzmaurice et al, 2015)
Magnetic resonance imaging (MRI) showed an increase in the primary tumor size at each evaluated time point, indicating that the gastroesophageal junction (GEJ) patient-derived orthotopic xenograft (PDOX) grew over time (Fig. 1A)
The orthotopic mouse model of esophageal/GEJ adenocarcinoma mimics the bioavailability of radiation and likely chemotherapy or targeted therapy in patients (Malaney et al, 2014; Stewart et al, 2015; Zhang et al, 2013)
Summary
Since the 1970s, gastroesophageal (GE) cancers are an increasing cause of cancer burden globally (Blot et al, 1991; Fitzmaurice et al, 2015). Despite recent treatment advances, including the use of neoadjuvant chemoradiation therapy (Mokdad et al, 2018), localized esophageal and/or gastroesophageal junction (GEJ) adenocarcinoma remains a highly aggressive cancer with 5-year survival rates of less than 30% (Fitzmaurice et al, 2015). One factor limiting improvements in treatment efficacy is a lack of preclinical models that recapitulate the growth pattern and radiological and pathological characteristics of patient tumors and that can be used to assess response to chemoradiation. Genetically engineered mouse models (GEMMs) (Becher and Holland, 2006) and patient-derived xenografts (PDXs) have emerged as promising translational platforms due to their resemblance to human tumors (Hidalgo et al, 2014; Siolas and Hannon, 2013). In the human GEJ, the nonkeratinizing esophageal squamous epithelium is formed between the distal
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