A novel orthotopic patient-derived xenograft model of radiation-induced glioma following medulloblastoma
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ABSTRACT:
PROVIDER: EGAD00010002017 | EGA |
REPOSITORIES: EGA
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Project description: Not available
| S-EPMC7600047 | biostudies-literature
Project description: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 phospho-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.
| EGAS00001004709 | EGA
Project description: Not available
| S-EPMC8099473 | biostudies-literature
Project description:We previously generated genetically engineered mouse (GEM) models based on perturbation of Tp53, Rb with or without Brca1 or Brca2 that develop serous epithelial ovarian cancer (SEOC) closely resembling the human disease on histologic and molecular levels. We have adapted these GEM models to orthotopic allografts that uniformly develop tumors with short latency in immunocompetent recipients and are ideally suited for routine preclinical studies. To monitor passaged tumors at the molecular level, we analyzed transcriptional profiles of a set of primary SEOC and matching derived passaged tumors. We have merged this dataset with previously published ( doi: 10.1158/0008-5472.CAN-11-3834; PMID 22617326) dataset of murine primary ovarian tumors from our GEM models (GSE46169) and merged and compared them to expression profiles of human dataset published previously (doi: 10.1038/nature10166). The high mortality rate from ovarian cancers can be attributed to late-stage diagnosis and lack of effective treatment. Despite enormous effort to develop better targeted therapies, platinum-based chemotherapy still remains the standard of care for ovarian cancer patients, and resistance occurs at a high rate. One of the rate limiting factors for translation of new drug discoveries into clinical treatments has been the lack of suitable preclinical cancer models with high predictive value. We previously generated genetically engineered mouse (GEM) models based on perturbation of Tp53, Rb with or without Brca1 or Brca2 that develop serous epithelial ovarian cancer (SEOC) closely resembling the human disease on histologic and molecular levels. Here, we describe an adaptation of these GEM models to orthotopic allografts that uniformly develop tumors with short latency and are ideally suited for routine preclinical studies. RNA was isolated from flash frozen ovarian tumors using Trizol and Qiagen RNeasy columns
2013-10-30 | E-GEOD-51927 | biostudies-arrayexpress
Project description:We previously generated genetically engineered mouse (GEM) models based on perturbation of Tp53, Rb with or without Brca1 or Brca2 that develop serous epithelial ovarian cancer (SEOC) closely resembling the human disease on histologic and molecular levels. We have adapted these GEM models to orthotopic allografts that uniformly develop tumors with short latency in immunocompetent recipients and are ideally suited for routine preclinical studies. To monitor passaged tumors at the molecular level, we analyzed transcriptional profiles of a set of primary SEOC and matching derived passaged tumors. We have merged this dataset with previously published ( doi: 10.1158/0008-5472.CAN-11-3834; PMID 22617326) dataset of murine primary ovarian tumors from our GEM models (GSE46169) and merged and compared them to expression profiles of human dataset published previously (doi: 10.1038/nature10166). The high mortality rate from ovarian cancers can be attributed to late-stage diagnosis and lack of effective treatment. Despite enormous effort to develop better targeted therapies, platinum-based chemotherapy still remains the standard of care for ovarian cancer patients, and resistance occurs at a high rate. One of the rate limiting factors for translation of new drug discoveries into clinical treatments has been the lack of suitable preclinical cancer models with high predictive value. We previously generated genetically engineered mouse (GEM) models based on perturbation of Tp53, Rb with or without Brca1 or Brca2 that develop serous epithelial ovarian cancer (SEOC) closely resembling the human disease on histologic and molecular levels. Here, we describe an adaptation of these GEM models to orthotopic allografts that uniformly develop tumors with short latency and are ideally suited for routine preclinical studies.
2013-10-30 | GSE51927 | GEO
Project description:Relapse and acquired drug resistance in T-cell acute lymphoblastic leukemia (T-ALL) remains a significant clinical problem. The current study used a pre-clinical model of induction therapy for pediatric ALL in NOD/SCID mice (Samuels et al Blood Cancer Journal (2014) 4, e232; doi:10.1038/bcj.2014.52) to study the development of drug resistance. We performed transcription profiling by array of human CD45-positive lymphocytes from patients with acute pediatric lymphoblastic leukemia, xenografted in NOD/SCID mice treated with vincristine, daunorubicin, dexamethasone and L-asparagine. Both the primary-patient-derived and xenograft cells were analysed. The VLXD2 treatment regime is described in full in the protocols associated with this submission and in Samuels et al (Blood Cancer Journal (2014) 4, e232; doi:10.1038/bcj.2014.52). This study is an extension of E-MEXP-3916.
2017-05-01 | E-MTAB-4759 | biostudies-arrayexpress
Project description:We generated novel patient derived xenograft (PDX) and cell line -derived xenograft models for pancreatic ductal adenocarcinoma (PDAC) which reflect different molecular subtypes. Pancreatic ductal adenocarcinoma is currently the tumor with the fourth highest mortality rate. Recently, subtypes of PDAC have been reported by Collisson et al (Nat. Med. 17(4) 2011. DOI: 10.1038/nm.2344). However current fetal calf serum (FCS) cultured cell lines do not accurately model these subtypes. We thus generated novel serum-free cell lines derived from primary patient xenografts. We here analyse the gene-expression profiles of the xenografts and the derived cell lines. We show that indeed three different subtypes can be separated in our models based on gene-expression data. Further, we identify upregulation of a drug-detoxification pathway specifically in xenografts and cell lines of one of the subtypes. These models and data will help to better understand inter-patient heterogeneity in PDAC and identify novel drug targets and diagnostic markers.
2016-01-12 | E-MTAB-4029 | biostudies-arrayexpress
Project description:DNA methylation likely plays a role in the regulation of human stress reactivity. In a genome-wide analysis of blood DNA methylation in 85 healthy individuals a locus in the Kit ligand (KITLG) gene (cg27512205) had the strongest association with cortisol stress reactivity (p=5.8x10-6). Replication was obtained in two independent samples, one using blood (N=45, p=0.001) and the other using buccal cells (N=255,p=0.004). KITLG methylation strongly mediated the relationship between childhood trauma and cortisol stress reactivity (32% mediation). Its genomic location (CpG island shore within an H3K27ac enhancer mark) provide further evidence that KITLG methylation is functionally relevant for the programming of stress reactivity. Our results extend preclinical evidence for epigenetic regulation of stress reactivity to humans and provide leads to enhance our understanding of the neurobiological pathways underlying stress vulnerability. Bisulphite converted DNA from whole blood of 85 healthy controls exposed to psychosocial stress task (TSST-G) was hybridised to the Illumina Infinium 450k Human Methylation Beadchip The DOI for this paper will be 10.1038/NCOMMS10967.
2016-03-16 | E-GEOD-77445 | biostudies-arrayexpress
Project description: Not available
| S-EPMC6012575 | biostudies-literature
Project description:Specific immune subsets from orthotopic murine rectal tumors were sequenced to explore the effect that short course radiotherapy has on the immune response.
2023-02-08 | GSE211991 | GEO