OLIG2 Is a Determinant for the Relapse of <i>MYC</i>-Amplified Medulloblastoma

Xu, Zhenhua; Murad, Najiba; Malawsky, Daniel; Tao, Ran; Rivero-Hinojosa, Samuel; Holdhof, Dörthe; Schüller, Ulrich; Zhang, Peng; Lazarski, Christopher A.; Rood, Brian R.; Packer, Roger J.; Gershon, Timothy R.; Pei, Yanxin

doi:10.1158/1078-0432.ccr-22-0527

Cited by 6 publications

(3 citation statements)

References 46 publications

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“…This difference in efficacy was expected based upon the correlation between OLIG2 and worse prognosis in patients with SHH-MB. However, OLIG2-expressing cells are also found in other subgroups [23] and that OLIG2 may contribute to tumor heterogeneity across MB disease subsets [50] , which may explain the response observed in the Group-3 Neo-113 model. We used the G-Smo GEMM model of SHH-MB to study in vivo CT-179 efficacy in tumors with heterogenous OLIG2 expression.…”

Section: Discussionmentioning

confidence: 99%

Preventing recurrence in Sonic Hedgehog Subgroup Medulloblastoma using OLIG2 inhibitor CT-179

Li,

Lim,

Dismuke

et al. 2023

Preprint

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Recurrence is the primary life-threatening complication for medulloblastoma (MB). In Sonic Hedgehog (SHH)-subgroup MB, OLIG2-expressing tumor stem cells drive recurrence. We investigated the anti-tumor potential of the small-molecule OLIG2 inhibitor CT-179, using SHH-MB patient-derived organoids, patient-derived xenograft (PDX) tumors and mice genetically-engineered to develop SHH-MB. CT-179 disrupted OLIG2 dimerization, DNA binding and phosphorylation and altered tumor cell cycle kinetics in vitro and in vivo, increasing differentiation and apoptosis. CT-179 increased survival time in GEMM and PDX models of SHH-MB, and potentiated radiotherapy in both organoid and mouse models, delaying post-radiation recurrence. Single cell transcriptomic studies (scRNA-seq) confirmed that CT-179 increased differentiation and showed that tumors up-regulated Cdk4 post-treatment. Consistent with increased CDK4 mediating CT-179 resistance, CT-179 combined with CDK4/6 inhibitor palbociclib delayed recurrence compared to either single-agent. These data show that targeting treatment-resistant MB stem cell populations by adding the OLIG2 inhibitor CT-179 to initial MB treatment can reduce recurrence.

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Section: Discussionmentioning

confidence: 99%

Preventing recurrence in Sonic Hedgehog Subgroup Medulloblastoma using OLIG2 inhibitor CT-179

Li,

Lim,

Dismuke

et al. 2023

Preprint

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“…Among the downregulated genes, PVALB passes through AKT/GSK-3β pathways that inhibit cell growth and induce cell death ( 26 ), and CLDN8 inhibits the proliferation, migration, and invasion of 786-O ccRCC cells through the EMT and AKT pathways ( 27 ). Among the upregulated genes, in the MYC amplified MB PDX model, tumors with low OLIG2 expression are radiation sensitive and have fewer relapses, while tumors with high OLIG2 expression have high radiation resistance and a significantly increased probability of recurrence ( 28 ), a predictive signature based on the expression of PI3 could be an independent prognostic factor for ccRCC ( 29 ). NANOS2 inhibits rheb by inhibiting transcription to inhibit mTORC1 activity, thereby inhibiting the cell cycle ( 30 ); SPRR1B is upregulated by the proinflammatory cytokines IL-1beta and IFN-gamma via p38 MAPK-mediated signaling pathways that lead to the activation of transcription factors CREB and ZEB1, respectively.…”

Section: Discussionmentioning

confidence: 99%

Expression of gasdermin D in clear cell renal cell carcinoma and its effect on its biological function

Zhang

Wang

et al. 2023

Front. Oncol.

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BackgroundClear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma, which suffers from the lack of diagnosis and treatment methods, and many patients cannot be diagnosed at first time. Gasdermin D (GSDMD) is involved in inflammatory reactions and pyroptosis and is considered a potential therapeutic target. This paper’s aim is to elucidate the expression of GSDMD in clear cell renal cell carcinoma and its value for treatment and prognosis, as well as its impact on the biological function of clear cell renal cell carcinoma.MethodThe Cancer Genome Atlas (TCGA) database was used to compare the expression of GSDMD in tumor and normal tissues, analyze its correlation with cancer stage and overall survival time, and establish receiver operating characteristic (ROC) curve, which was confirmed by the Gene Expression Omnibus (GEO) database and immunohistochemical staining of clinical samples and PCR and Western blotting (WB) of cell lines. The relationship between GSDMD and patient prognosis and staging was analyzed using TCGA database and validated using clinical sample data. Differentially expressed genes (DEGs) and epithelial–mesenchymal transition (EMT)-related genes of GSDMD were screened by TCGA database. Protein–protein interaction (PPI) of GSDMD was constructed by GeneMANIA and STRING, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were analyzed by the Metascape database. Then, R software was used to analyze the immune cell infiltration, immune microenvironment score, and tumor mutational burden (TMB) analysis of GSDMD high- and low-expression groups in TCGA database. GSDMD lentivirus was used to transfect 769-P cells to construct stable upregulated and downregulated transfected cell lines. PCR was used to verify the expression differences of differentially expressed genes between the high- and low-expression groups of GSDMD; then, MTT, flow apoptosis, and Transwell were used to detect the proliferation, apoptosis, invasion, and migration of the transfected cells.ResultsThe results of bioinformatics analysis showed that the expression of GSDMD in clear cell renal cell carcinoma was significantly correlated with patient stage and overall survival, and the tumor with high expression of GSDMD had a worse stage and overall survival. GSDMD has some significance in the diagnosis of ccRCC. The results of EMT correlation analysis and enrichment analysis showed that GSDMD was correlated with genes and pathways related to invasion and metastasis of renal cell carcinoma. The subsequent immune cell infiltration analysis showed that there were many differences in the infiltration of immune cells between the high- and low-expression groups of GSDMD, such as naive B cells. The immune microenvironment score showed that the high-expression group had a lower proportion of stromal cells than the local expression group but had a higher proportion of immune cells. Through TMB, it was shown that the high-expression group had a higher mutation. The expression of GSDMD in renal cell carcinoma by immunohistochemistry and in vitro cell experiments was confirmed. According to the prognostic information of clinical patients, it was found that GSDMD was significantly correlated with TNM stage, Fuhrman grade, lymph node metastasis, gender, and smoking or not, and the prognosis of patients with high expression of GSDMD was worse. After that, we constructed stable transfection cell lines with high expression and knockdown through lentivirus transfection and verified the expression amount of differentially expressed genes by PCR, which is consistent with the results of TCGA database. Then, we confirmed that GSDMD is related to proliferation, invasion, migration, and apoptosis of ccRCC by MTT, flow apoptosis, and Transwell assay. The low expression of GSDMD inhibits the proliferation, invasion, and migration of tumors and enhances apoptosis and vice versa. Therefore, GSDMD can be used as a potential biological marker for the diagnosis and prognosis of ccRCC.

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“…Another glial transcription factor, OLIG2 is also suggested to be of importance in this setting, driving relapse after irradiation treatment, specifically in MYC amplified MB [83]. However, in contrast to SOX9 leading to MYC downregulation, OLIG2 was linked to co-expression with MYC suggesting different roles in perhaps different states of the relapse process (Figure 2).…”

Section: Group 3 Medulloblastomamentioning

confidence: 99%

Drivers Underlying Metastasis and Relapse in Medulloblastoma and Targeting Strategies

Holmberg,

Borgenvik,

Zhao

et al. 2024

Cancers

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Medulloblastomas comprise a molecularly diverse set of malignant pediatric brain tumors in which patients are stratified according to different prognostic risk groups that span from very good to very poor. Metastasis at diagnosis is most often a marker of poor prognosis and the relapse incidence is higher in these children. Medulloblastoma relapse is almost always fatal and recurring cells have, apart from resistance to standard of care, acquired genetic and epigenetic changes that correlate with an increased dormancy state, cell state reprogramming and immune escape. Here, we review means to carefully study metastasis and relapse in preclinical models, in light of recently described molecular subgroups. We will exemplify how therapy resistance develops at the cellular level, in a specific niche or from therapy-induced secondary mutations. We further describe underlying molecular mechanisms on how tumors acquire the ability to promote leptomeningeal dissemination and discuss how they can establish therapy-resistant cell clones. Finally, we describe some of the ongoing clinical trials of high-risk medulloblastoma and suggest or discuss more individualized treatments that could be of benefit to specific subgroups.

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OLIG2 Is a Determinant for the Relapse of MYC-Amplified Medulloblastoma

Cited by 6 publications

References 46 publications

Preventing recurrence in Sonic Hedgehog Subgroup Medulloblastoma using OLIG2 inhibitor CT-179

Preventing recurrence in Sonic Hedgehog Subgroup Medulloblastoma using OLIG2 inhibitor CT-179

Expression of gasdermin D in clear cell renal cell carcinoma and its effect on its biological function

Drivers Underlying Metastasis and Relapse in Medulloblastoma and Targeting Strategies

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