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Cellular microenvironment and tumor suppressor control of tumor development in genetic and xenograft mouse models of glioblastoma
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Jara, Kelly. Cellular microenvironment and tumor suppressor control of tumor development in genetic and xenograft mouse models of glioblastoma. Retrieved from https://doi.org/doi:10.7282/t3-etmv-w619

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TitleCellular microenvironment and tumor suppressor control of tumor development in genetic and xenograft mouse models of glioblastoma
NameJara, Kelly (author); Sabaawy, Hatem (chair); Pine, Sharon (member); Shi, Jia (member); Rutgers University; School of Graduate Studies
Date Created2022
Other Date2022-05 (degree)
SubjectCellular biology, Biology, Genetics, GEMM, Glioblastoma, Mouse model, PDOX, TAM, Xenograft
Extent85 pages : illustrations
DescriptionGlioblastoma is the most common primary brain malignancy, yet overall patient survival has not improved by more than months in the last decade. The standard treatment for these tumors includes surgical resection, radiation, and chemotherapy which provides a median survival of only about 15 months. Despite this aggressive treatment strategy, these tumors almost universally recur. More comprehensive study of GBM biology, mechanisms of GBM therapeutic resistance, and novel therapeutic targets are needed to improve patient outcomes. For this urgent need, we set out to develop preclinical mouse models for the study of GBM. First, we employed the commonly utilized subcutaneous (SC) and brain orthotopic patient-derived xenograft (PDX) mouse models and assessed their ability to recapitulate the cellular microenvironment and features of GBM, so they can be utilized as clinically relevant models for developing new therapies. Second, we developed a set of genetically engineered mouse models (GEMM) to help address some of the translational gaps apparent in PDX models. We found our PDX mouse tumors retained histological features of the original patient tumor. When examining the surrounding tumor microenvironment (TME), we discovered that our orthotopic (PDOX) model was superior to the heterotopic, SC (PDX) model in reproducing TME features of patient tumors due to the presence of brain-specific TME cells, with astrocytes and microglia features. Utilizing fluorescent and immunohistochemical analyses, we demonstrate the contribution of brain orthotopic microglia and astrocytes to the invasive zone of GBM. We report that PDOX mice represent a powerful tool for studying TME cell-tumor interactions and are more clinically relevant for examining precision medicine therapies. Next, we established conditional GEMM using the CreER-lox system to study the contribution of tumor suppressors to glioma development in mice. Induction of tumor suppressor knockout upon tamoxifen treatment was verified in the brain of adult mice and resulted in phenotypic changes associated with glioma development. We further developed brain derived organoids from neonatal and adult GEMM to delineate the tumor suppressor loss in mouse organoids. These GEMM provide a novel model for glioma to study the molecular signaling mechanisms in immune competent hosts and a superb resource when further developed for examining immunotherapy and combination targeted therapy, directed against the molecular vulnerabilities found in patients, for developing new treatments for GBM.
NoteM.S.
NoteIncludes bibliographical references
Genretheses
Persistent URLhttps://doi.org/doi:10.7282/t3-etmv-w619
LanguageEnglish
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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