Inhibition of Gli2 suppresses tumorigenicity in glioblastoma stem cells derived from a de novo murine brain cancer model

Tanigawa, Shin‐ichi; Fujita, Mitsugu; Moyama, Chiami; Ando, Shota; Hiromi,; Kojima, Yasushi; Fujishita, Teruaki; Aoki, Masahiro; Takeuchi, Hayato; Yamanaka, T.; Takahashi, Yusuke; Hashimoto, Naoya; Nakata, Susumu

doi:10.1038/s41417-020-00282-5

Cited by 14 publications

(14 citation statements)

References 52 publications

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“…Our data suggest that, because of the depletion of the SOX2 cell population from tumors, inhibition of SHH signaling at the level of GLI would provide a more stable disease remission than targeting SMO. Limiting the translational relevance of our data, none of the GLI inhibitors used thus far have a pharmacokinetic profile suitable for brain tumor patients, as neither I-BET151 ( 40 ) nor Gant-61 ( 41 ) are brain penetrant and JQ-1 has a short half-life ( 43 ). Therefore, we studied whether the BET inhibitor, BMS-986158, currently undergoing clinical evaluation on pediatric and adult malignancies (NCT02419417, NCT03936465, and NCT04817007) could similarly block SHH signaling at the level of GLI and therefore provide long-lasting MB remission.…”

Section: Resultsmentioning

confidence: 91%

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Noncanonical activation of GLI signaling in SOX2 ⁺ cells drives medulloblastoma relapse

et al. 2022

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SRY (sex determining region Y)–box 2 (SOX2)–labeled cells play key roles in chemoresistance and tumor relapse; thus, it is critical to elucidate the mechanisms propagating them. Single-cell transcriptomic analyses of the most common malignant pediatric brain tumor, medulloblastoma (MB), revealed the existence of astrocytic Sox2 + cells expressing sonic hedgehog (SHH) signaling biomarkers. Treatment with vismodegib, an SHH inhibitor that acts on Smoothened (Smo), led to increases in astrocyte-like Sox2 + cells. Using SOX2-enriched MB cultures, we observed that SOX2 + cells required SHH signaling to propagate, and unlike in the proliferative tumor bulk, the SHH pathway was activated in these cells downstream of Smo in an MYC-dependent manner. Functionally different GLI inhibitors depleted vismodegib-resistant SOX2 + cells from MB tissues, reduced their ability to further engraft in vivo, and increased symptom-free survival. Our results emphasize the promise of therapies targeting GLI to deplete SOX2 + cells and provide stable tumor remission.

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Section: Resultsmentioning

confidence: 91%

“…Given that neither I-BET151 ( 40 ) nor Gant-61 ( 41 ) are likely to cross the blood-brain barrier, limiting their efficacy to subcutaneous MB models, we turned to the drug JQ-1 as an alternative BET inhibitor, which could demonstrate efficacy in the brain ( 42 ). Similar to I-BET151 or Gant-61, JQ-1 attenuated the proliferation ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Noncanonical activation of GLI signaling in SOX2 ⁺ cells drives medulloblastoma relapse

et al. 2022

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“…These drivers include Notch, HH and WNT pathways. Previous studies suggested that these signaling pathways may perform cross-talk with SHH signaling pathways (27,71,(80)(81)89,90), which means that these signaling pathways may be activated simultaneously in different tumor types. WNT/β-catenin interacts with the SHH pathway through GLI1 and GLI2 by regulating the expression of secreted crimp-related proteins.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to influencing mTORC1/2 and HH pathway interactions, GLI2 also affects HH and Wnt pathways and has an important role in GBM stem cell (GSC) maintenance. GLI2 knockdown using lentiviral-mediated shRNA downregulated HH-related and Wnt signaling pathway-related genes, including leucine-rich repeat-containing G-protein coupled receptor 5, inhibited tumor cell proliferation and invasive capacity, and induced apoptosis ( 81 ). Takezaki et al ( 7 ) indicated that overexpression of GLI2DC, a C-terminal truncated form of GLI2, antagonized GLI transcription factor function, inhibited glioma-initiating cell proliferation in culture and neoplasms occurring in organisms; glioma-initiating cell proliferation was prevented by clipping glial downstream factor cell division cycle 2 (CDC2).…”

Section: Molecular Mechanisms Of the Hh Signaling Pathway In Gbmmentioning

confidence: 99%

Hedgehog signaling regulates the development and treatment of glioblastoma (Review)

et al. 2022

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Glioblastoma (GBM) is the most common and fatal malignant tumor type of the central nervous system. GBM affects public health and it is important to identify biomarkers to improve diagnosis, reduce drug resistance and improve prognosis (e.g., personalized targeted therapies). Hedgehog (HH) signaling has an important role in embryonic development, tissue regeneration and stem cell renewal. A large amount of evidence indicates that both normative and non-normative HH signals have an important role in GBM. The present study reviewed the role of the HH signaling pathway in the occurrence and progression of GBM. Furthermore, the effectiveness of drugs that target different components of the HH pathway was also examined. The HH pathway has an important role in reversing drug resistance after GBM conventional treatment. The present review highlighted the relevance of HH signaling in GBM and outlined that this pathway has a key role in the occurrence, development and treatment of GBM. Contents 1. Introduction 2. Overview of GBM 3. The HH signaling pathway 4. Molecular mechanisms of the HH signaling pathway in GBM 5. Targeting the HH signaling pathway in GBM 6. HH pathway and immunotherapy 7. Discussion 8. Conclusion

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“…The first includes the SCMH1 gene, associated with the Polycomb group (PcG) multiprotein complexes, required to maintain the transcriptionally repressive state of some genes [ 57 ]. The second region includes the GLI2 gene, which promotes cell proliferation and migration in glioma [ 58 , 59 ]. Other potentially interesting regions are two gains, in 11p11.2 and 16p13.3, shared by two PBZs and evidenced also in other TCs and/or GSCs from other patients.…”

Section: Discussionmentioning

confidence: 99%

Characterizing the Genomic Profile in High-Grade Gliomas: From Tumor Core to Peritumoral Brain Zone, Passing through Glioma-Derived Tumorspheres

Giambra

Messuti

Cristofori

et al. 2021

Biology

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Glioblastoma is an extremely heterogeneous disease. Treatment failure and tumor recurrence primarily reflect the presence in the tumor core (TC) of the glioma stem cells (GSCs), and secondly the contribution, still to be defined, of the peritumoral brain zone (PBZ). Using the array-CGH platform, we deepened the genomic knowledge about the different components of GBM and we identified new specific biomarkers useful for new therapies. We firstly investigated the genomic profile of 20 TCs of GBM; then, for 14 cases and 7 cases, respectively, we compared these genomic profiles with those of the related GSC cultures and PBZ biopsies. The analysis on 20 TCs confirmed the intertumoral heterogeneity and a high percentage of copy number alterations (CNAs) in GBM canonical pathways. Comparing the genomic profiles of 14 TC-GSC pairs, we evidenced a robust similarity among the two samples of each patient. The shared imbalanced genes are related to the development and progression of cancer and in metabolic pathways, as shown by bioinformatic analysis using DAVID. Finally, the comparison between 7 TC-PBZ pairs leads to the identification of PBZ-unique alterations that require further investigation.

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Inhibition of Gli2 suppresses tumorigenicity in glioblastoma stem cells derived from a de novo murine brain cancer model

Cited by 14 publications

References 52 publications

Noncanonical activation of GLI signaling in SOX2 ⁺ cells drives medulloblastoma relapse

Noncanonical activation of GLI signaling in SOX2 ⁺ cells drives medulloblastoma relapse

Hedgehog signaling regulates the development and treatment of glioblastoma (Review)

Characterizing the Genomic Profile in High-Grade Gliomas: From Tumor Core to Peritumoral Brain Zone, Passing through Glioma-Derived Tumorspheres

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Inhibition of Gli2 suppresses tumorigenicity in glioblastoma stem cells derived from a de novo murine brain cancer model

Cited by 14 publications

References 52 publications

Noncanonical activation of GLI signaling in SOX2 + cells drives medulloblastoma relapse

Noncanonical activation of GLI signaling in SOX2 + cells drives medulloblastoma relapse

Hedgehog signaling regulates the development and treatment of glioblastoma (Review)

Characterizing the Genomic Profile in High-Grade Gliomas: From Tumor Core to Peritumoral Brain Zone, Passing through Glioma-Derived Tumorspheres

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Noncanonical activation of GLI signaling in SOX2 ⁺ cells drives medulloblastoma relapse

Noncanonical activation of GLI signaling in SOX2 ⁺ cells drives medulloblastoma relapse