Medulloblastoma (MB) is the most common malignant brain tumor in children. Patients whose tumors exhibit overexpression or amplification of the MYC oncogene (c-MYC) usually have an extremely poor prognosis, but there are no animal models of this subtype of the disease. Here we show that cerebellar stem cells expressing Myc and mutant Trp53 (p53) generate aggressive tumors following orthotopic transplantation. These tumors consist of large, pleiomorphic cells and resemble human MYC-driven MB at a molecular level. Notably, antagonists of PI3K/mTOR signaling, but not Hedgehog signaling, inhibit growth of tumor cells. These findings suggest that cerebellar stem cells can give rise to MYC-driven MB, and identify a novel model that can be used to test therapies for this devastating disease.
An animal model of MYC-driven medulloblastoma.
Specimen part
View SamplesThe synthetic supercooling drug, icilin, and its primary receptor target, the cation channel transient receptor potential (TRP) melastatin-8 (TRPM8), have been described as potent negative regulators of inflammation in the colon. The aim of this study was to determine whether the anti-inflammatory action of icilin could potentially be used to treat autoimmune neuroinflammatory disorders, such as multiple sclerosis (MS). During experimental autoimmune encephalomyelitis (EAE)a CD4+ T celldriven murine model of MSwe found that both wild-type (WT) and TRPM8-deficient EAE mice were protected from disease progression during icilin treatment, as evidenced by delays in clinical onset and reductions in neuroinflammation. In vitro, icilin potently inhibited the proliferation of murine and human CD4+ T cells, with the peripheral expansion of autoantigen-restricted T cells similarly diminished by the administration of icilin in mice. Attenuation of both TRPM8-/- and TRP ankyrin-1-/- T cell proliferation by icilin was consistent with the WT phenotype, which suggests a mechanism that is independent of these channels. In addition, icilin treatment altered the expressional profile of activated CD4+ T cells to one that was indicative of restricted effector function and limited neuroinflammatory potential. These findings identify a potent anti-inflammatory role for icilin in lymphocyte-mediated neuroinflammation and highlight clear pleiotropic effects of the compound beyond classic TRP channel activation.
The cooling compound icilin attenuates autoimmune neuroinflammation through modulation of the T-cell response.
Sex, Specimen part
View SamplesTransfection of a Kaposi's sarcoma (KS) herpesvirus (KSHV) Bacterial Artificial Chromosome (KSHVBac36) into mouse bone marrow endothelial lineage cells generated a cell (mECK36) that induced KS-like tumors in mice. mECK36 formed KSHV-harboring vascularized spindle-cell sarcomas that were LANA+ and displayed a KSHV and host transcriptomes reminiscent of KS tumors.
In vivo-restricted and reversible malignancy induced by human herpesvirus-8 KSHV: a cell and animal model of virally induced Kaposi's sarcoma.
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View SamplesNF-kB has been linked to doxorubicin-based chemotherapy resistance in breast cancer patients. NF-kB nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined, however its functional consequences in terms the spectrum of NF-kB -dependent genes expressed and, thus, the impact on tumour cell behaviour are unclear.
Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-кB target genes in human breast cancer.
Cell line, Treatment
View SamplesEpigenetic regulation of gene expression by histone modification has emerged as a major facet of physiologic and disease processes. As a result, there has been intense interest in developing epigenetic therapies leading to the discovery of small molecule agents that target proteins involved in histone modification. Several histone deacetylase (HDAC) inhibitors are now approved drugs for a specialized group of hematologic malignancies but not yet for a wider range of cancer types including solid tumors. One of the conceptual challenges in targeting HDACs is that even selective class I HDAC inhibitors likely impact these deacetylase activities indiscriminately across a range of distinct HDAC-containing multiprotein complexes. Such broad cellular effects may result in a narrow therapeutic window between disease efficacy and toxicity. Among HDAC complexes, the CoREST complex, which includes HDAC1 or its close paralog HDAC2, the scaffolding protein CoREST, and lysine specific demethylase 1 (LSD1) has attracted special interest. Here we report corin2, designed to dually inhibit the CoREST complex major enzymatic activities, lysine specific demethylase 1 (LSD1) and HDACs 1/2. Corin2 is a synthetic hybrid agent derived from the class I HDAC inhibitor (entinostat) and an LSD1 inhibitor (tranylcypromine analog). Enzymologic analysis reveals that corin2 selectively targets the CoREST complex and shows more sustained inhibition of the CoREST complex HDAC activity than entinostat. Cell-based experiments demonstrate that corin2 exhibits a superior anti-proliferative profile against several melanoma lines compared to its parent monofunctional HDAC and LSD1 inhibitors (alone or in combination) but is less toxic to non-cancerous primary human melanocytes. Transcriptomics analysis shows that corin2 is a more powerful inducer of tumor suppressor genes relative to the parent HDAC and LSD1 compounds (alone or in combination). Genetic knockdown of CoREST or LSD1 in cancer cell lines abolishes the differences in potency of corin2 vs. entinostat, suggesting that corin2's favorable pharmacologic effects rely on an intact CoREST complex. Corin2 was also effective in slowing tumor growth in a melanoma mouse xenograft model. These studies highlight the promise of a new class of two-pronged hybrid agents that selectively target particular epigenetic regulatory complexes and offer unique therapeutic opportunities.
Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors.
Cell line
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