A novel patient-derived orthotopic xenograft model of esophageal adenocarcinoma provides a platform for translational discoveries
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
The Company of Biologists
2019-12-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/12/12/dmm041004 |
| _version_ | 1817982762288676864 |
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| author | Omkara Lakshmi Veeranki Zhimin Tong Alicia Mejia Anuj Verma Riham Katkhuda Roland Bassett Tae-Beom Kim Jing Wang Wenhua Lang Barbara Mino Luisa Solis Charles Kingsley William Norton Ramesh Tailor Ji Yuan Wu Sunil Krishnan Steven H. Lin Mariela Blum Wayne Hofstetter Jaffer Ajani Scott Kopetz Dipen Maru |
| author_facet | Omkara Lakshmi Veeranki Zhimin Tong Alicia Mejia Anuj Verma Riham Katkhuda Roland Bassett Tae-Beom Kim Jing Wang Wenhua Lang Barbara Mino Luisa Solis Charles Kingsley William Norton Ramesh Tailor Ji Yuan Wu Sunil Krishnan Steven H. Lin Mariela Blum Wayne Hofstetter Jaffer Ajani Scott Kopetz Dipen Maru |
| author_sort | Omkara Lakshmi Veeranki |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T23:25:33Z |
| format | Article |
| id | doaj.art-c8c0cfc3d13c42e8a428a009925cdd42 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-04-13T23:25:33Z |
| publishDate | 2019-12-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-c8c0cfc3d13c42e8a428a009925cdd422022-12-22T02:25:06ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112019-12-01121210.1242/dmm.041004041004A novel patient-derived orthotopic xenograft model of esophageal adenocarcinoma provides a platform for translational discoveriesOmkara Lakshmi Veeranki0Zhimin Tong1Alicia Mejia2Anuj Verma3Riham Katkhuda4Roland Bassett5Tae-Beom Kim6Jing Wang7Wenhua Lang8Barbara Mino9Luisa Solis10Charles Kingsley11William Norton12Ramesh Tailor13Ji Yuan Wu14Sunil Krishnan15Steven H. Lin16Mariela Blum17Wayne Hofstetter18Jaffer Ajani19Scott Kopetz20Dipen Maru21 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 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.http://dmm.biologists.org/content/12/12/dmm041004patient-derived orthotopic xenograft mouse modelesophageal adenocarcinomagastroesophageal junction cancermouse modelsmicroenvironment |
| spellingShingle | Omkara Lakshmi Veeranki Zhimin Tong Alicia Mejia Anuj Verma Riham Katkhuda Roland Bassett Tae-Beom Kim Jing Wang Wenhua Lang Barbara Mino Luisa Solis Charles Kingsley William Norton Ramesh Tailor Ji Yuan Wu Sunil Krishnan Steven H. Lin Mariela Blum Wayne Hofstetter Jaffer Ajani Scott Kopetz Dipen Maru A novel patient-derived orthotopic xenograft model of esophageal adenocarcinoma provides a platform for translational discoveries Disease Models & Mechanisms patient-derived orthotopic xenograft mouse model esophageal adenocarcinoma gastroesophageal junction cancer mouse models microenvironment |
| title | A novel patient-derived orthotopic xenograft model of esophageal adenocarcinoma provides a platform for translational discoveries |
| title_full | A novel patient-derived orthotopic xenograft model of esophageal adenocarcinoma provides a platform for translational discoveries |
| title_fullStr | A novel patient-derived orthotopic xenograft model of esophageal adenocarcinoma provides a platform for translational discoveries |
| title_full_unstemmed | A novel patient-derived orthotopic xenograft model of esophageal adenocarcinoma provides a platform for translational discoveries |
| title_short | A novel patient-derived orthotopic xenograft model of esophageal adenocarcinoma provides a platform for translational discoveries |
| title_sort | novel patient derived orthotopic xenograft model of esophageal adenocarcinoma provides a platform for translational discoveries |
| topic | patient-derived orthotopic xenograft mouse model esophageal adenocarcinoma gastroesophageal junction cancer mouse models microenvironment |
| url | http://dmm.biologists.org/content/12/12/dmm041004 |
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