Investigating Radiotherapy Response in a Novel Syngeneic Model of Prostate Cancer
The prostate cancer (PCa) field lacks clinically relevant, syngeneic mouse models which retain the tumour microenvironment observed in PCa patients. This study establishes a cell line from prostate tumour tissue derived from the <i>Pten<sup>−/−</sup>/trp53<sup>−/−</sup>...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-09-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/12/10/2804 |
| _version_ | 1797552201445408768 |
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| author | Charles M. Haughey Debayan Mukherjee Rebecca E. Steele Amy Popple Lara Dura-Perez Adam Pickard Mehjabin Patel Suneil Jain Paul B. Mullan Rich Williams Pedro Oliveira Niamh E. Buckley Jamie Honeychurch Simon S. McDade Timothy Illidge Ian G. Mills Sharon L. Eddie |
| author_facet | Charles M. Haughey Debayan Mukherjee Rebecca E. Steele Amy Popple Lara Dura-Perez Adam Pickard Mehjabin Patel Suneil Jain Paul B. Mullan Rich Williams Pedro Oliveira Niamh E. Buckley Jamie Honeychurch Simon S. McDade Timothy Illidge Ian G. Mills Sharon L. Eddie |
| author_sort | Charles M. Haughey |
| collection | DOAJ |
| description | The prostate cancer (PCa) field lacks clinically relevant, syngeneic mouse models which retain the tumour microenvironment observed in PCa patients. This study establishes a cell line from prostate tumour tissue derived from the <i>Pten<sup>−/−</sup>/trp53<sup>−/−</sup></i> mouse, termed DVL3 which when subcutaneously implanted in immunocompetent C57BL/6 mice, forms tumours with distinct glandular morphology, strong cytokeratin 8 and androgen receptor expression, recapitulating high-risk localised human PCa. Compared to the commonly used TRAMP C1 model, generated with SV40 large T-antigen, DVL3 tumours are immunologically cold, with a lower proportion of CD8+ T-cells, and high proportion of immunosuppressive myeloid derived suppressor cells (MDSCs), thus resembling high-risk PCa. Furthermore, DVL3 tumours are responsive to fractionated RT, a standard treatment for localised and metastatic PCa, compared to the TRAMP C1 model. RNA-sequencing of irradiated DVL3 tumours identified upregulation of type-1 interferon and STING pathways, as well as transcripts associated with MDSCs. Upregulation of STING expression in tumour epithelium and the recruitment of MDSCs following irradiation was confirmed by immunohistochemistry. The DVL3 syngeneic model represents substantial progress in preclinical PCa modelling, displaying pathological, micro-environmental and treatment responses observed in molecular high-risk disease. Our study supports using this model for development and validation of treatments targeting PCa, especially novel immune therapeutic agents. |
| first_indexed | 2024-03-10T15:57:37Z |
| format | Article |
| id | doaj.art-2c9282bbbde1491f89dc9d0d4badd84e |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T15:57:37Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2c9282bbbde1491f89dc9d0d4badd84e2023-11-20T15:32:32ZengMDPI AGCancers2072-66942020-09-011210280410.3390/cancers12102804Investigating Radiotherapy Response in a Novel Syngeneic Model of Prostate CancerCharles M. Haughey0Debayan Mukherjee1Rebecca E. Steele2Amy Popple3Lara Dura-Perez4Adam Pickard5Mehjabin Patel6Suneil Jain7Paul B. Mullan8Rich Williams9Pedro Oliveira10Niamh E. Buckley11Jamie Honeychurch12Simon S. McDade13Timothy Illidge14Ian G. Mills15Sharon L. Eddie16Patrick G Johnston Centre for Cancer Research, Queen’s University, Belfast BT9 7AE, UKTargeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester M13 9PL, UKPatrick G Johnston Centre for Cancer Research, Queen’s University, Belfast BT9 7AE, UKTargeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester M13 9PL, UKPatrick G Johnston Centre for Cancer Research, Queen’s University, Belfast BT9 7AE, UKPatrick G Johnston Centre for Cancer Research, Queen’s University, Belfast BT9 7AE, UKTargeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester M13 9PL, UKPatrick G Johnston Centre for Cancer Research, Queen’s University, Belfast BT9 7AE, UKPatrick G Johnston Centre for Cancer Research, Queen’s University, Belfast BT9 7AE, UKPatrick G Johnston Centre for Cancer Research, Queen’s University, Belfast BT9 7AE, UKThe Christie Hospital Foundation Trust, Manchester M20 4BX, UKPatrick G Johnston Centre for Cancer Research, Queen’s University, Belfast BT9 7AE, UKTargeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester M13 9PL, UKPatrick G Johnston Centre for Cancer Research, Queen’s University, Belfast BT9 7AE, UKTargeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester M13 9PL, UKPatrick G Johnston Centre for Cancer Research, Queen’s University, Belfast BT9 7AE, UKPatrick G Johnston Centre for Cancer Research, Queen’s University, Belfast BT9 7AE, UKThe prostate cancer (PCa) field lacks clinically relevant, syngeneic mouse models which retain the tumour microenvironment observed in PCa patients. This study establishes a cell line from prostate tumour tissue derived from the <i>Pten<sup>−/−</sup>/trp53<sup>−/−</sup></i> mouse, termed DVL3 which when subcutaneously implanted in immunocompetent C57BL/6 mice, forms tumours with distinct glandular morphology, strong cytokeratin 8 and androgen receptor expression, recapitulating high-risk localised human PCa. Compared to the commonly used TRAMP C1 model, generated with SV40 large T-antigen, DVL3 tumours are immunologically cold, with a lower proportion of CD8+ T-cells, and high proportion of immunosuppressive myeloid derived suppressor cells (MDSCs), thus resembling high-risk PCa. Furthermore, DVL3 tumours are responsive to fractionated RT, a standard treatment for localised and metastatic PCa, compared to the TRAMP C1 model. RNA-sequencing of irradiated DVL3 tumours identified upregulation of type-1 interferon and STING pathways, as well as transcripts associated with MDSCs. Upregulation of STING expression in tumour epithelium and the recruitment of MDSCs following irradiation was confirmed by immunohistochemistry. The DVL3 syngeneic model represents substantial progress in preclinical PCa modelling, displaying pathological, micro-environmental and treatment responses observed in molecular high-risk disease. Our study supports using this model for development and validation of treatments targeting PCa, especially novel immune therapeutic agents.https://www.mdpi.com/2072-6694/12/10/2804tumour microenvironmentsyngeneic modelprostate cancerradiotherapypreclinical modellingmyeloid-derived suppressor cells |
| spellingShingle | Charles M. Haughey Debayan Mukherjee Rebecca E. Steele Amy Popple Lara Dura-Perez Adam Pickard Mehjabin Patel Suneil Jain Paul B. Mullan Rich Williams Pedro Oliveira Niamh E. Buckley Jamie Honeychurch Simon S. McDade Timothy Illidge Ian G. Mills Sharon L. Eddie Investigating Radiotherapy Response in a Novel Syngeneic Model of Prostate Cancer Cancers tumour microenvironment syngeneic model prostate cancer radiotherapy preclinical modelling myeloid-derived suppressor cells |
| title | Investigating Radiotherapy Response in a Novel Syngeneic Model of Prostate Cancer |
| title_full | Investigating Radiotherapy Response in a Novel Syngeneic Model of Prostate Cancer |
| title_fullStr | Investigating Radiotherapy Response in a Novel Syngeneic Model of Prostate Cancer |
| title_full_unstemmed | Investigating Radiotherapy Response in a Novel Syngeneic Model of Prostate Cancer |
| title_short | Investigating Radiotherapy Response in a Novel Syngeneic Model of Prostate Cancer |
| title_sort | investigating radiotherapy response in a novel syngeneic model of prostate cancer |
| topic | tumour microenvironment syngeneic model prostate cancer radiotherapy preclinical modelling myeloid-derived suppressor cells |
| url | https://www.mdpi.com/2072-6694/12/10/2804 |
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