In vivo loss of tumorigenicity in a patient-derived orthotopic xenograft mouse model of ependymoma
IntroductionEpendymomas (EPN) are the third most common malignant brain cancer in children. Treatment strategies for pediatric EPN have remained unchanged over recent decades, with 10-year survival rates stagnating at just 67% for children aged 0-14 years. Moreover, a proportion of patients who surv...
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1123492/full |
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| author | Jacqueline P. Whitehouse Jacqueline P. Whitehouse Hilary Hii Chelsea Mayoh Chelsea Mayoh Marie Wong Marie Wong Pamela Ajuyah Paulette Barahona Louise Cui Hetal Dholaria Hetal Dholaria Hetal Dholaria Christine L. White Christine L. White Christine L. White Molly K. Buntine Molly K. Buntine Jacob Byrne Keteryne Rodrigues da Silva Keteryne Rodrigues da Silva Meegan Howlett Meegan Howlett Emily J. Girard Emily J. Girard Maria Tsoli Maria Tsoli David S. Ziegler David S. Ziegler David S. Ziegler Jason M. Dyke Jason M. Dyke Sharon Lee Paul G. Ekert Paul G. Ekert Paul G. Ekert Paul G. Ekert Paul G. Ekert Mark J. Cowley Mark J. Cowley Nicholas G. Gottardo Nicholas G. Gottardo Nicholas G. Gottardo Raelene Endersby Raelene Endersby |
| author_facet | Jacqueline P. Whitehouse Jacqueline P. Whitehouse Hilary Hii Chelsea Mayoh Chelsea Mayoh Marie Wong Marie Wong Pamela Ajuyah Paulette Barahona Louise Cui Hetal Dholaria Hetal Dholaria Hetal Dholaria Christine L. White Christine L. White Christine L. White Molly K. Buntine Molly K. Buntine Jacob Byrne Keteryne Rodrigues da Silva Keteryne Rodrigues da Silva Meegan Howlett Meegan Howlett Emily J. Girard Emily J. Girard Maria Tsoli Maria Tsoli David S. Ziegler David S. Ziegler David S. Ziegler Jason M. Dyke Jason M. Dyke Sharon Lee Paul G. Ekert Paul G. Ekert Paul G. Ekert Paul G. Ekert Paul G. Ekert Mark J. Cowley Mark J. Cowley Nicholas G. Gottardo Nicholas G. Gottardo Nicholas G. Gottardo Raelene Endersby Raelene Endersby |
| author_sort | Jacqueline P. Whitehouse |
| collection | DOAJ |
| description | IntroductionEpendymomas (EPN) are the third most common malignant brain cancer in children. Treatment strategies for pediatric EPN have remained unchanged over recent decades, with 10-year survival rates stagnating at just 67% for children aged 0-14 years. Moreover, a proportion of patients who survive treatment often suffer long-term neurological side effects as a result of therapy. It is evident that there is a need for safer, more effective treatments for pediatric EPN patients. There are ten distinct subgroups of EPN, each with their own molecular and prognostic features. To identify and facilitate the testing of new treatments for EPN, in vivo laboratory models representative of the diverse molecular subtypes are required. Here, we describe the establishment of a patient-derived orthotopic xenograft (PDOX) model of posterior fossa A (PFA) EPN, derived from a metastatic cranial lesion.MethodsPatient and PDOX tumors were analyzed using immunohistochemistry, DNA methylation profiling, whole genome sequencing (WGS) and RNA sequencing.ResultsBoth patient and PDOX tumors classified as PFA EPN by methylation profiling, and shared similar histological features consistent with this molecular subgroup. RNA sequencing revealed that gene expression patterns were maintained across the primary and metastatic tumors, as well as the PDOX. Copy number profiling revealed gains of chromosomes 7, 8 and 19, and loss of chromosomes 2q and 6q in the PDOX and matched patient tumor. No clinically significant single nucleotide variants were identified, consistent with the low mutation rates observed in PFA EPN. Overexpression of EZHIP RNA and protein, a common feature of PFA EPN, was also observed. Despite the aggressive nature of the tumor in the patient, this PDOX was unable to be maintained past two passages in vivo.DiscussionOthers who have successfully developed PDOX models report some of the lowest success rates for EPN compared to other pediatric brain cancer types attempted, with loss of tumorigenicity not uncommon, highlighting the challenges of propagating these tumors in the laboratory. Here, we discuss our collective experiences with PFA EPN PDOX model generation and propose potential approaches to improve future success in establishing preclinical EPN models. |
| first_indexed | 2024-04-10T05:56:49Z |
| format | Article |
| id | doaj.art-009c2573d20c46b8a58d763a746781a4 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-10T05:56:49Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-009c2573d20c46b8a58d763a746781a42023-03-03T09:25:28ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-03-011310.3389/fonc.2023.11234921123492In vivo loss of tumorigenicity in a patient-derived orthotopic xenograft mouse model of ependymomaJacqueline P. Whitehouse0Jacqueline P. Whitehouse1Hilary Hii2Chelsea Mayoh3Chelsea Mayoh4Marie Wong5Marie Wong6Pamela Ajuyah7Paulette Barahona8Louise Cui9Hetal Dholaria10Hetal Dholaria11Hetal Dholaria12Christine L. White13Christine L. White14Christine L. White15Molly K. Buntine16Molly K. Buntine17Jacob Byrne18Keteryne Rodrigues da Silva19Keteryne Rodrigues da Silva20Meegan Howlett21Meegan Howlett22Emily J. Girard23Emily J. Girard24Maria Tsoli25Maria Tsoli26David S. Ziegler27David S. Ziegler28David S. Ziegler29Jason M. Dyke30Jason M. Dyke31Sharon Lee32Paul G. Ekert33Paul G. Ekert34Paul G. Ekert35Paul G. Ekert36Paul G. Ekert37Mark J. Cowley38Mark J. Cowley39Nicholas G. Gottardo40Nicholas G. Gottardo41Nicholas G. Gottardo42Raelene Endersby43Raelene Endersby44Brain Tumour Research Program, Telethon Kids Institute, Nedlands, WA, AustraliaCentre for Child Health Research, University of Western Australia, Nedlands, WA, AustraliaBrain Tumour Research Program, Telethon Kids Institute, Nedlands, WA, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, AustraliaSchool of Clinical Medicine, University of New South Wales (UNSW) Sydney, Kensington, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, AustraliaSchool of Clinical Medicine, University of New South Wales (UNSW) Sydney, Kensington, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, AustraliaBrain Tumour Research Program, Telethon Kids Institute, Nedlands, WA, AustraliaDepartment of Paediatric and Adolescent Oncology/Haematology, Perth Children’s Hospital, Nedlands, WA, AustraliaDivision of Paediatrics, University of Western Australia Medical School, Nedlands, WA, AustraliaGenetics and Molecular Pathology Laboratory, Hudson Institute of Medical Research, Clayton, VIC, AustraliaDepartment of Molecular and Translational Science, Monash University, Clayton, VIC, AustraliaDivision of Genetics and Genomics, Victorian Clinical Genetics Services, Parkville, VIC, AustraliaGenetics and Molecular Pathology Laboratory, Hudson Institute of Medical Research, Clayton, VIC, AustraliaDepartment of Molecular and Translational Science, Monash University, Clayton, VIC, AustraliaBrain Tumour Research Program, Telethon Kids Institute, Nedlands, WA, AustraliaBrain Tumour Research Program, Telethon Kids Institute, Nedlands, WA, Australia0Medical School of Rbeirão Preto (FMRP-USP), University of São Paulo, São Paulo, BrazilBrain Tumour Research Program, Telethon Kids Institute, Nedlands, WA, AustraliaCentre for Child Health Research, University of Western Australia, Nedlands, WA, Australia1Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States2Ben Towne Center for Childhood Cancer Research, Seattle Children’s Research Institute, Seattle, WA, United StatesChildren’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, AustraliaSchool of Clinical Medicine, University of New South Wales (UNSW) Sydney, Kensington, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, AustraliaSchool of Clinical Medicine, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia3Kids Cancer Centre, Sydney Children’s Hospital, Randwick, NSW, Australia4Department of Neuropathology, PathWest Laboratory Medicine, Royal Perth Hospital, Perth, WA, Australia5Pathology and Laboratory Medicine, University of Western Australia, Nedlands, WA, Australia6Department of Neurosurgery, Perth Children’s Hospital, Nedlands, WA, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, AustraliaSchool of Clinical Medicine, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia7Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC, Australia8Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia9The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, AustraliaSchool of Clinical Medicine, University of New South Wales (UNSW) Sydney, Kensington, NSW, AustraliaBrain Tumour Research Program, Telethon Kids Institute, Nedlands, WA, AustraliaCentre for Child Health Research, University of Western Australia, Nedlands, WA, AustraliaDepartment of Paediatric and Adolescent Oncology/Haematology, Perth Children’s Hospital, Nedlands, WA, AustraliaBrain Tumour Research Program, Telethon Kids Institute, Nedlands, WA, AustraliaCentre for Child Health Research, University of Western Australia, Nedlands, WA, AustraliaIntroductionEpendymomas (EPN) are the third most common malignant brain cancer in children. Treatment strategies for pediatric EPN have remained unchanged over recent decades, with 10-year survival rates stagnating at just 67% for children aged 0-14 years. Moreover, a proportion of patients who survive treatment often suffer long-term neurological side effects as a result of therapy. It is evident that there is a need for safer, more effective treatments for pediatric EPN patients. There are ten distinct subgroups of EPN, each with their own molecular and prognostic features. To identify and facilitate the testing of new treatments for EPN, in vivo laboratory models representative of the diverse molecular subtypes are required. Here, we describe the establishment of a patient-derived orthotopic xenograft (PDOX) model of posterior fossa A (PFA) EPN, derived from a metastatic cranial lesion.MethodsPatient and PDOX tumors were analyzed using immunohistochemistry, DNA methylation profiling, whole genome sequencing (WGS) and RNA sequencing.ResultsBoth patient and PDOX tumors classified as PFA EPN by methylation profiling, and shared similar histological features consistent with this molecular subgroup. RNA sequencing revealed that gene expression patterns were maintained across the primary and metastatic tumors, as well as the PDOX. Copy number profiling revealed gains of chromosomes 7, 8 and 19, and loss of chromosomes 2q and 6q in the PDOX and matched patient tumor. No clinically significant single nucleotide variants were identified, consistent with the low mutation rates observed in PFA EPN. Overexpression of EZHIP RNA and protein, a common feature of PFA EPN, was also observed. Despite the aggressive nature of the tumor in the patient, this PDOX was unable to be maintained past two passages in vivo.DiscussionOthers who have successfully developed PDOX models report some of the lowest success rates for EPN compared to other pediatric brain cancer types attempted, with loss of tumorigenicity not uncommon, highlighting the challenges of propagating these tumors in the laboratory. Here, we discuss our collective experiences with PFA EPN PDOX model generation and propose potential approaches to improve future success in establishing preclinical EPN models.https://www.frontiersin.org/articles/10.3389/fonc.2023.1123492/fullependymomaposterior fossapatient-derivedxenograftmolecularpediatric cancer |
| spellingShingle | Jacqueline P. Whitehouse Jacqueline P. Whitehouse Hilary Hii Chelsea Mayoh Chelsea Mayoh Marie Wong Marie Wong Pamela Ajuyah Paulette Barahona Louise Cui Hetal Dholaria Hetal Dholaria Hetal Dholaria Christine L. White Christine L. White Christine L. White Molly K. Buntine Molly K. Buntine Jacob Byrne Keteryne Rodrigues da Silva Keteryne Rodrigues da Silva Meegan Howlett Meegan Howlett Emily J. Girard Emily J. Girard Maria Tsoli Maria Tsoli David S. Ziegler David S. Ziegler David S. Ziegler Jason M. Dyke Jason M. Dyke Sharon Lee Paul G. Ekert Paul G. Ekert Paul G. Ekert Paul G. Ekert Paul G. Ekert Mark J. Cowley Mark J. Cowley Nicholas G. Gottardo Nicholas G. Gottardo Nicholas G. Gottardo Raelene Endersby Raelene Endersby In vivo loss of tumorigenicity in a patient-derived orthotopic xenograft mouse model of ependymoma Frontiers in Oncology ependymoma posterior fossa patient-derived xenograft molecular pediatric cancer |
| title | In vivo loss of tumorigenicity in a patient-derived orthotopic xenograft mouse model of ependymoma |
| title_full | In vivo loss of tumorigenicity in a patient-derived orthotopic xenograft mouse model of ependymoma |
| title_fullStr | In vivo loss of tumorigenicity in a patient-derived orthotopic xenograft mouse model of ependymoma |
| title_full_unstemmed | In vivo loss of tumorigenicity in a patient-derived orthotopic xenograft mouse model of ependymoma |
| title_short | In vivo loss of tumorigenicity in a patient-derived orthotopic xenograft mouse model of ependymoma |
| title_sort | in vivo loss of tumorigenicity in a patient derived orthotopic xenograft mouse model of ependymoma |
| topic | ependymoma posterior fossa patient-derived xenograft molecular pediatric cancer |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1123492/full |
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