Core pathway mutations induce de-differentiation of murine astrocytes into glioblastoma stem cells that are sensitive to radiation but resistant to temozolomide

Schmid, Ralf S.; Simon, Jeremy M.; Vitucci, Mark; McNeill, Robert S.; Bash, Ryan; Werneke, Andrea M.; Huey, Lauren; White, Kristen; Ewend, Matthew G.; Wu, Jing; Miller, C. Ryan

doi:10.1093/neuonc/nov321

Cited by 28 publications

(46 citation statements)

References 62 publications

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“…Moreover, intrinsic properties of the tumor cells within these subtypes may contribute to the observed differences in treatment response. It has been shown that oligodendroglioma cells are more responsive to TMZ than astrocytic glioma cells (Schindelin et al, ; Schmid et al, ). Since our Olig2 staining and histological analysis demonstrated that the PDGFB‐overexpressing model has oligodendroglial features, and our GFAP staining and histological analysis showed that the NF1‐silenced model has astrocytoma features, this point may account for some of the differences in TMZ response seen in our models.…”

Section: Discussionmentioning

confidence: 99%

Genetic driver mutations define the expression signature and microenvironmental composition of high‐grade gliomas

Herting

Chen

Pitter

et al. 2017

Glia

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High-grade gliomas (HGG), including glioblastomas, are characterized by invasive growth, resistance to therapy, and high inter- and intra-tumoral heterogeneity. The key histological hallmarks of glioblastoma are pseudopalisading necrosis and microvascular proliferation, which allow pathologists to distinguish glioblastoma from lower-grade gliomas. In addition to being genetically and molecularly heterogeneous, HGG are also heterogeneous with respect to the composition of their microenvironment. The question of whether this microenvironmental heterogeneity is driven by the molecular identity of the tumor remains controversial. However, this question is of utmost importance since microenvironmental, non-neoplastic cells are key components of the most radiotherapy- and chemotherapy-resistant niches of the tumor. Our work demonstrates a versatile, reliable, and reproducible adult HGG mouse model with NF1-silencing as a driver mutation. This model shows significant differences in tumor microenvironment, expression of subtype-specific markers, and response to standard therapy when compared to our established PDGFB-overexpressing HGG mouse model. PDGFB-overexpressing and NF1-silenced murine tumors closely cluster with human proneural and mesenchymal subtypes, as well as PDGFRA-amplified and NF1-deleted/mutant human tumors, respectively, at both the RNA and protein expression levels. These models can be generated in fully immunocompetent mixed or C57BL/6 genetic background mice, and therefore can easily be incorporated into preclinical studies for cancer cell-specific or immune cell-targeting drug discovery studies.

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Section: Discussionmentioning

confidence: 99%

Genetic driver mutations define the expression signature and microenvironmental composition of high‐grade gliomas

Herting

Chen

Pitter

et al. 2017

Glia

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“…We have shown that TRP mutations induce a primitive, proneural GBM-like gene expression state in cultured murine astrocytes (63). We subsequently found that cultured TRP astrocytes acquire the functional properties of NSC in vitro and cancer stem cells in vivo (51). These results suggest that TRP mutations induce astrocyte dedifferentiation.…”

Section: Trp Mutations Induce Expression Of the Nsc Marker Nestin In mentioning

confidence: 82%

“…We have previously shown that transformation of cultured astrocytes by TRP mutations induces a primitive transcriptome state in vitro (63). We have also found that TRP astrocytes acquire the functional properties of NSC in vitro and cancer stem cells in vivo (51). Here, we show that TRP mutations induce the expression of the primitive maker nestin in situ (Figure 6).…”

Section: Discussionmentioning

confidence: 93%

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Intrinsic Astrocyte Heterogeneity Influences Tumor Growth in Glioma Mouse Models

et al. 2016

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The influence of cellular origin on glioma pathogenesis remains elusive. We previously showed that mutations inactivating Rb and Pten and activating Kras transform astrocytes and induce tumorigenesis throughout the adult mouse brain. However, it remained unclear whether astrocyte subpopulations were susceptible to these mutations. We therefore used genetic lineage tracing and fate mapping in adult conditional, inducible genetically engineered mice to monitor transformation of glial fibrillary acidic protein (GFAP) and glutamate aspartate transporter (GLAST) astrocytes and immunofluorescence to monitor cellular composition of the tumor microenvironment over time. Because considerable regional heterogeneity exists among astrocytes, we also examined the influence of brain region on tumor growth. GFAP astrocyte transformation induced uniformly rapid, regionally independent tumor growth, but transformation of GLAST astrocytes induced slowly growing tumors with significant regional bias. Transformed GLAST astrocytes had reduced proliferative response in culture and in vivo and malignant progression was delayed in these tumors. Recruited glial cells, including proliferating astrocytes, oligodendrocyte progenitors and microglia, were the majority of GLAST, but not GFAP astrocyte-derived tumors and their abundance dynamically changed over time. These results suggest that intrinsic astrocyte heterogeneity, and perhaps regional brain microenvironment, significantly contributes to glioma pathogenesis.

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“…The OTSSP167 and DZNep were utilized as the MELK and EZH2 inhibitors to complement these findings, which have been involved in a great deal of research (39)(40)(41). On the 5th day after intracranial transplantation of dissociated MB25550 CSCs, engraftments were confirmed with microMRI scanning, and mice with equivalent volumes were randomized into three groups for intraperitoneal treatment: OTSSP167 (20 mg/kg), DZNep (20 mg/kg), and control (n ¼ 6/group).…”

Section: Transplantation and Drug Administrationmentioning

confidence: 99%

MELK and EZH2 Cooperate to Regulate Medulloblastoma Cancer Stem-like Cell Proliferation and Differentiation

Liu

Sun

et al. 2017

Molecular Cancer Research

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Medulloblastoma is the most common malignant brain tumor in children. Although accumulated research has suggested that cancer stem-like cells play a key role in medulloblastoma tumorigenesis, the specific molecular mechanism regarding proliferation remains elusive. Here, we reported more abundant expression of maternal embryonic leucine-zipper kinase (MELK) and enhancer of zeste homolog 2 (EZH2) in medulloblastoma stemlike cells than in neural stem cells and the interaction between the two proteins could mediate the self-renewal of sonic hedgehog subtype medulloblastoma. In human medulloblastoma, extensive nodularity and large-cell/anaplastic subgroups differed according to the staining levels of MELK and EZH2 from the other two subgroups. The proportion of MELK-or EZH2-positive staining status could be considered as a potential indicator for survival. Mechanistically, MELK bound to and phosphorylated EZH2, and its methylation was induced by EZH2 in medulloblastoma, which could regulate the proliferation of cancer stemlike cells. In xenografts, loss of MELK or EZH2 attenuated medulloblastoma stem-like cell-derived tumor growth and promoted differentiation. These findings indicate that MELK-induced phosphorylation and EZH2-mediated methylation in MELK/EZH2 pathway are essential for medulloblastoma stem-like cell-derived tumor proliferation, thereby identifying a potential therapeutic strategy for these patients.Implications: This study demonstrates that the interaction occurring between MELK and EZH2 promotes self-proliferation and stemness, thus representing an attractive therapeutic target and potential candidate for diagnosis of medulloblastoma.Mol Cancer Res; 15(9); 1275-86. Ó2017 AACR.

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Core pathway mutations induce de-differentiation of murine astrocytes into glioblastoma stem cells that are sensitive to radiation but resistant to temozolomide

Cited by 28 publications

References 62 publications

Genetic driver mutations define the expression signature and microenvironmental composition of high‐grade gliomas

Genetic driver mutations define the expression signature and microenvironmental composition of high‐grade gliomas

Intrinsic Astrocyte Heterogeneity Influences Tumor Growth in Glioma Mouse Models

MELK and EZH2 Cooperate to Regulate Medulloblastoma Cancer Stem-like Cell Proliferation and Differentiation

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