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A Novel Orthotopic Patient-Derived Xenograft Model of Radiation-Induced Glioma Following Medulloblastoma.

ABSTRACT: Radiation-induced glioma (RIG) is a highly aggressive brain cancer arising as a consequence of radiation therapy. We report a case of RIG that arose in the brain stem following treatment for paediatric medulloblastoma, and the development and characterisation of a matched orthotopic patient-derived xenograft (PDX) model (TK-RIG915). Patient and PDX tumours were analysed using DNA methylation profiling, whole genome sequencing (WGS) and RNA sequencing. While initially thought to be a diffuse intrinsic pontine glioma (DIPG) based on disease location, results from methylation profiling and WGS were not consistent with this diagnosis. Furthermore, clustering analyses based on RNA expression suggested the tumours were distinct from primary DIPG. Additional gene expression analysis demonstrated concordance with a published RIG expression profile. Multiple genetic alterations that enhance PI3K/AKT and Ras/Raf/MEK/ERK signalling were discovered in TK-RIG915 including an activating mutation in PIK3CA, upregulation of PDGFRA and AKT2, inactivating mutations in NF1, and a gain-of-function mutation in PTPN11. Additionally, deletion of CDKN2A/B, increased IDH1 expression, and decreased ARID1A expression were observed. Detection of phosphorylated S6, 4EBP1 and ERK via immunohistochemistry confirmed PI3K pathway and ERK activation. Here, we report one of the first PDX models for RIG, which recapitulates the patient disease and is molecularly distinct from primary brain stem glioma. Genetic interrogation of this model has enabled the identification of potential therapeutic vulnerabilities in this currently incurable disease.

SUBMITTER: Whitehouse JP

PROVIDER: S-EPMC7600047 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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A Novel Orthotopic Patient-Derived Xenograft Model of Radiation-Induced Glioma Following Medulloblastoma.

Whitehouse Jacqueline P JP Howlett Meegan M Hii Hilary H Mayoh Chelsea C Wong Marie M Barahona Paulette P Ajuyah Pamela P White Christine L CL Buntine Molly K MK Dyke Jason M JM Lee Sharon S Valvi Santosh S Stanley Jason J Andradas Clara C Carline Brooke B Kuchibhotla Mani M Ekert Paul G PG Cowley Mark J MJ Gottardo Nicholas G NG Endersby Raelene R

Cancers 20201012 10

Radiation-induced glioma (RIG) is a highly aggressive brain cancer arising as a consequence of radiation therapy. We report a case of RIG that arose in the brain stem following treatment for paediatric medulloblastoma, and the development and characterisation of a matched orthotopic patient-derived xenograft (PDX) model (TK-RIG915). Patient and PDX tumours were analysed using DNA methylation profiling, whole genome sequencing (WGS) and RNA sequencing. While initially thought to be a diffuse intr ...[more]

PMID: 33053751

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Project description:Patient‑derived orthotopic glioma xenograft models are important platforms used for pre‑clinical research of glioma. In the present study, the diagnostic ability of magnetic resonance imaging (MRI) was examined with regard to the identification of biomarkers obtained from patient‑derived glioma xenografts and human tumors. Conventional MRI, diffusion weighted imaging and dynamic contrast‑enhanced (DCE)‑MRI were used to analyze seven pairs of high grade gliomas with their corresponding xenografts obtained from non‑obese diabetic‑severe‑combined immunodeficiency nude mice. Tumor samples were collected for transcriptome sequencing and histopathological staining, and differentially expressed genes were screened between the original tumors and the corresponding xenografts. Gene Ontology (GO) analysis was performed to predict the functions of these genes. In 6 cases of xenografts with diffuse growth, the degree of enhancement was significantly lower compared with the original tumors. Histopathological staining indicated that the microvascular area and microvascular diameter of the xenografts were significantly lower compared with the original tumors (P=0.009 and P=0.007, respectively). In one case, there was evidence of nodular tumor growth in the mouse. Both MRI and histopathological staining showed a clear demarcation between the transplanted tumors and the normal brain tissues. The relative apparent diffusion coefficient values of the 7 cases examined were significantly higher compared with the corresponding original tumors (P=0.001) and transfer coefficient values derived from DCE‑MRI of the tumor area was significantly lower compared with the original tumors (P=0.016). GO analysis indicated that the expression levels of extracellular matrix‑associated genes, angiogenesis‑associated genes and immune function‑associated genes in the original tumors were higher compared with the corresponding xenografts. In conclusion, the data demonstrated that the MRI features of patient‑derived xenograft glioma models in mice were different compared with those of the original patient tumors. Differential gene expression may underlie the differences noted in the MRI features between original tumors and corresponding xenografts. The results of the present study highlight the precautions that should be taken when extrapolating data from patient‑derived xenograft studies, and their applicability to humans.

Project description:BackgroundMetastatic uveal melanoma is a highly fatal disease; most patients die from their hepatic metastasis within 1 year. A major drawback in the development of new treatments for metastatic uveal melanoma is the difficulty in obtaining appropriate cell lines and the lack of appropriate animal models. Patient-derived xenograft (PDX) tumor models, bearing ectopically implanted tumors at a subcutaneous site, have been developed. However, these ectopically implanted PDX models have obstacles to translational research, including a low engraftment rate, slow tumor growth, and biological changes after multiple passages due to the different microenvironment. To overcome these limitations, we developed a new method to directly transplant biopsy specimens to the liver of immunocompromised mice.ResultsBy using two metastatic uveal melanoma cell lines, we demonstrated that the liver provides a more suitable microenvironment for tumor growth compared to subcutaneous sites and that surgical orthotopic implantation (SOI) of tumor pieces allows the creation of a liver tumor in immunocompromised mice. Subsequently, 10 of 12 hepatic metastasis specimens from patients were successfully xenografted into the immunocompromised mice (83.3% success rate) using SOI, including 8 of 10 needle biopsy specimens (80%). Additionally, four cryopreserved PDX tumors were re-implanted to new mice and re-establishment of PDX tumors was confirmed in all four mice. The serially passaged xenograft tumors as well as the re-implanted tumors after cryopreservation were similar to the original patient tumors in histologic, genomic, and proteomic expression profiles. CT imaging was effective for detecting and monitoring PDX tumors in the liver of living mice. The expression of Ki67 in original patient tumors was a predictive factor for implanted tumor growth and the success of serial passages in PDX mice.ConclusionsSurgical orthotopic implantation of hepatic metastasis from uveal melanoma is highly successful in the establishment of orthotopic PDX models, enhancing their practical utility for research applications. By using CT scan, tumor growth can be monitored, which is beneficial to evaluate treatment effects in interventional studies.

Dataset Information

A Novel Orthotopic Patient-Derived Xenograft Model of Radiation-Induced Glioma Following Medulloblastoma.

Publications

A Novel Orthotopic Patient-Derived Xenograft Model of Radiation-Induced Glioma Following Medulloblastoma.

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