Frontiers in Oncology (Mar 2023)
In vivo loss of tumorigenicity in a patient-derived orthotopic xenograft mouse model of ependymoma
- 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
Affiliations
- Jacqueline P. Whitehouse
- Brain Tumour Research Program, Telethon Kids Institute, Nedlands, WA, Australia
- Jacqueline P. Whitehouse
- Centre for Child Health Research, University of Western Australia, Nedlands, WA, Australia
- Hilary Hii
- Brain Tumour Research Program, Telethon Kids Institute, Nedlands, WA, Australia
- Chelsea Mayoh
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia
- Chelsea Mayoh
- School of Clinical Medicine, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
- Marie Wong
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia
- Marie Wong
- School of Clinical Medicine, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
- Pamela Ajuyah
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia
- Paulette Barahona
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia
- Louise Cui
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia
- Hetal Dholaria
- Brain Tumour Research Program, Telethon Kids Institute, Nedlands, WA, Australia
- Hetal Dholaria
- Department of Paediatric and Adolescent Oncology/Haematology, Perth Children’s Hospital, Nedlands, WA, Australia
- Hetal Dholaria
- Division of Paediatrics, University of Western Australia Medical School, Nedlands, WA, Australia
- Christine L. White
- Genetics and Molecular Pathology Laboratory, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Christine L. White
- Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
- Christine L. White
- Division of Genetics and Genomics, Victorian Clinical Genetics Services, Parkville, VIC, Australia
- Molly K. Buntine
- Genetics and Molecular Pathology Laboratory, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Molly K. Buntine
- Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
- Jacob Byrne
- Brain Tumour Research Program, Telethon Kids Institute, Nedlands, WA, Australia
- Keteryne Rodrigues da Silva
- Brain Tumour Research Program, Telethon Kids Institute, Nedlands, WA, Australia
- Keteryne Rodrigues da Silva
- 0Medical School of Rbeirão Preto (FMRP-USP), University of São Paulo, São Paulo, Brazil
- Meegan Howlett
- Brain Tumour Research Program, Telethon Kids Institute, Nedlands, WA, Australia
- Meegan Howlett
- Centre for Child Health Research, University of Western Australia, Nedlands, WA, Australia
- Emily J. Girard
- 1Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
- Emily J. Girard
- 2Ben Towne Center for Childhood Cancer Research, Seattle Children’s Research Institute, Seattle, WA, United States
- Maria Tsoli
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia
- Maria Tsoli
- School of Clinical Medicine, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
- David S. Ziegler
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia
- David S. Ziegler
- School of Clinical Medicine, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
- David S. Ziegler
- 3Kids Cancer Centre, Sydney Children’s Hospital, Randwick, NSW, Australia
- Jason M. Dyke
- 4Department of Neuropathology, PathWest Laboratory Medicine, Royal Perth Hospital, Perth, WA, Australia
- Jason M. Dyke
- 5Pathology and Laboratory Medicine, University of Western Australia, Nedlands, WA, Australia
- Sharon Lee
- 6Department of Neurosurgery, Perth Children’s Hospital, Nedlands, WA, Australia
- Paul G. Ekert
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia
- Paul G. Ekert
- School of Clinical Medicine, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
- Paul G. Ekert
- 7Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC, Australia
- Paul G. Ekert
- 8Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Paul G. Ekert
- 9The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
- Mark J. Cowley
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia
- Mark J. Cowley
- School of Clinical Medicine, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
- Nicholas G. Gottardo
- Brain Tumour Research Program, Telethon Kids Institute, Nedlands, WA, Australia
- Nicholas G. Gottardo
- Centre for Child Health Research, University of Western Australia, Nedlands, WA, Australia
- Nicholas G. Gottardo
- Department of Paediatric and Adolescent Oncology/Haematology, Perth Children’s Hospital, Nedlands, WA, Australia
- Raelene Endersby
- Brain Tumour Research Program, Telethon Kids Institute, Nedlands, WA, Australia
- Raelene Endersby
- Centre for Child Health Research, University of Western Australia, Nedlands, WA, Australia
- DOI
- https://doi.org/10.3389/fonc.2023.1123492
- Journal volume & issue
-
Vol. 13
Abstract
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.
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