Functional Genomics Identifies Tis21-Dependent Mechanisms and Putative Cancer Drug Targets Underlying Medulloblastoma Shh-Type Development

Gentile, Giulia; Ceccarelli, Manuela; Micheli, Laura; Tirone, Felice; Cavallaro, Sebastiano

doi:10.3389/fphar.2016.00449

Cited by 5 publications

(5 citation statements)

References 231 publications

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“…Our cohort displayed similar features to previous studies regarding the aggressiveness of G3 tumors (23,30,50,57,58,60). G3 and G4 MBs were more closely related than WNT and SHH and appear as non-WNT/non-SHH in the revised 2016 WHO classification, but historically these tumors are molecularly and clinically heterogeneous (10,18,44,49,50,59,61).…”

Section: Discussionsupporting

confidence: 83%

“…The prognoses of SHH-activated MBs are less favorable; SHH-MBs have an intact blood-brain barrier (BBB) and are less responsive to chemotherapy compared to WNT-MBs (22,26,27). Many SHH-MBs are age-dependent, with those aged ≥17 months more likely to harbor SMO and PTCH1 mutations (18,(28)(29)(30)(31)(32). Subgroup-driven clinical trials are currently underway to assess the efficacy of SHH pathway inhibitors such as vismodegib at diagnosis or in recurrent or refractory SHH-activated tumors.…”

Section: Introductionmentioning

confidence: 99%

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Methylation Profiling of Medulloblastoma in a Clinical Setting Permits Sub-classification and Reveals New Outcome Predictions

et al. 2020

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Medulloblastoma (MB) is the most common childhood malignant brain tumor and is a leading cause of cancer-related death in children. DNA methylation profiling has rapidly advanced our understanding of MB pathogenesis at the molecular level, but assessments in Saudi Arabian (SA)-MB cases are sparse. MBs can be sub-grouped according to methylation patterns from FPPE samples into Wingless (WNT-MB), Sonic Hedgehog (SHH-MB), Group 3 (G3), and Group 4 (G4) tumors. The WNT-MB and SHH-MB subgroups are characterized by gain-of function mutations that activate oncogenic cell signaling, whilst G3/G4 tumors show recurrent chromosomal alterations. Given that each subgroup has distinct clinical outcomes, the ability to subgroup SA-FPPE samples holds significant prognostic and therapeutic value. Here, we performed the first assessment of MB-DNA methylation patterns in an SA cohort using archival biopsy material (FPPE n = 49). Of the 41 materials available for methylation assessments, 39 could be classified into the major DNA methylation subgroups (SHH, WNT, G3, and G4). Furthermore, methylation analysis was able to reclassify tumors that could not be sub-grouped through next-generation sequencing, highlighting its superior accuracy for MB molecular classifications. Independent assessments demonstrated known clinical relationships of the subgroups, exemplified by the high survival rates observed for WNT tumors. Surprisingly, the G4 subgroup did not conform to previously identified phenotypes, with a high prevalence in females, high metastatic rates, and a large number of tumor-associated deaths. Taking our results together, we demonstrate that DNA methylation profiling enables the robust sub-classification of four disease sub-groups in archival FFPE biopsy material from SA-MB patients. Moreover, we Alharbi et al. Clincal Methylation Profiling of Medulloblastomashow that the incorporation of DNA methylation biomarkers can significantly improve current disease-risk stratification schemes, particularly concerning the identification of aggressive G4 tumors. These findings have important implications for future clinical disease management in MB cases across the Arab world.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Methylation Profiling of Medulloblastoma in a Clinical Setting Permits Sub-classification and Reveals New Outcome Predictions

et al. 2020

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“…Thus, different pathways are likely to be involved. In this regard, a recent analysis of genomic pathways in the Ptch1 +/- / Tis21 -/- mouse model suggests that the chemotaxis mechanism of the GCPs by the Cxcl3-Cxcr2 axis may be clathrin-dependent (Gentile et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

Suppression of Medulloblastoma Lesions by Forced Migration of Preneoplastic Precursor Cells with Intracerebellar Administration of the Chemokine Cxcl3

2016

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Medulloblastoma (MB), tumor of the cerebellum, remains a leading cause of cancer-related mortality in childhood. We previously showed, in a mouse model of spontaneous MB (Ptch1+/-/Tis21-/-), that a defect of the migration of cerebellar granule neuron precursor cells (GCPs) correlates with an increased frequency of MB. This occurs because GCPs, rather than migrating internally and differentiating, remain longer in the proliferative area at the cerebellar surface, becoming targets of transforming insults. Furthermore, we identified the chemokine Cxcl3 as responsible for the inward migration of GCPs. As it is known that preneoplastic GCPs (pGCPs) can still migrate and differentiate like normal GCPs, thus exiting the neoplastic program, in this study we tested the hypothesis that pGCPs within a MB lesion could be induced by Cxcl3 to migrate and differentiate. We observed that the administration of Cxcl3 for 28 days within the cerebellum of 1-month-old Ptch1+/-/Tis21-/- mice, i.e., when MB lesions are already formed, leads to complete disappearance of the lesions. However, a shorter treatment with Cxcl3 (2 weeks) was ineffective, suggesting that the suppression of MB lesions is dependent on the duration of Cxcl3 application. We verified that the treatment with Cxcl3 causes a massive migration of pGCPs from the lesion to the internal granular layer, where they differentiate. Thus, the induction of migration of pGCPs in MB lesions may open new ways to treat MB that exploit the plasticity of the pGCPs, forcing their differentiation. It remains to be tested whether this plasticity continues at advanced stages of MB. If so, these findings would set a potential use of the chemokine Cxcl3 as therapeutic agent against MB development in human preclinical studies.

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“…Arrows represent activation; bars represent inhibition. The stars indicate the potential drug targets, identified through the genomic analysis of deregulated Ptch1 +/− /Tis21 KO -dependent genes, as previously proposed (32). AKT, AKR mouse thymoma kinase; Cxcl, C-X-C motif chemokine ligand; Cxcr, C-X-C motif chemokine receptor; Deptor, DEP domain-containing mTOR-interacting protein; Dgkq, diacylglycerol kinase theta; Eif, eukaryotic translation initiation factor; eif-4EBP, eukaryotic translation initiation factor 4E-binding protein; IL-8, interleukin 8; Lars, leucyl-tRNA synthetase; mTOR, mammalian target of rapamycin; p70S6K, p70 ribosomal protein S6 kinase; Pdgfd, platelet-derived growth factor D; Pdgfrb, platelet-derived growth factor receptor beta; PI3K, phosphatidylinositol-3-kinase; PTEN, phosphatase and tensin homolog; Rab11Fip2, Ras-related binding protein 11 family-interacting protein 2; Rraga, Ras-related GTP-binding protein A; S6, ribosomal protein S6; Sik2, salt-inducible kinase 2; Smg1, nonsense-mediated mRNA decay-associated PI3K-related kinase; Src, steroid receptor coactivator; Timp1, tissue inhibitor of metalloproteinases-1.…”

Section: Resultsmentioning

confidence: 99%

Tumor Growth in the High Frequency Medulloblastoma Mouse Model Ptch1+/−/Tis21KO Has a Specific Activation Signature of the PI3K/AKT/mTOR Pathway and Is Counteracted by the PI3K Inhibitor MEN1611

et al. 2021

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We have previously generated a mouse model (Ptch1+/−/Tis21KO), which displays high frequency spontaneous medulloblastoma, a pediatric tumor of the cerebellum. Early postnatal cerebellar granule cell precursors (GCPs) of this model show, in consequence of the deletion of Tis21, a defect of the Cxcl3-dependent migration. We asked whether this migration defect, which forces GCPs to remain in the proliferative area at the cerebellar surface, would be the only inducer of their high frequency transformation. In this report we show, by further bioinformatic analysis of our microarray data of Ptch1+/−/Tis21KO GCPs, that, in addition to the migration defect, they show activation of the PI3K/AKT/mTOR pathway, as the mRNA levels of several activators of this pathway (e.g., Lars, Rraga, Dgkq, Pdgfd) are up-regulated, while some inhibitors (e.g. Smg1) are down-regulated. No such change is observed in the Ptch1+/− or Tis21KO background alone, indicating a peculiar synergy between these two genotypes. Thus we investigated, by mRNA and protein analysis, the role of PI3K/AKT/mTOR signaling in MBs and in nodules from primary Ptch1+/−/Tis21KO MB allografted in the flanks of immunosuppressed mice. Activation of the PI3K/AKT/mTOR pathway is seen in full-blown Ptch1+/−/Tis21KO MBs, relative to Ptch1+/−/Tis21WT MBs. In Ptch1+/−/Tis21KO MBs we observe that the proliferation of neoplastic GCPs increases while apoptosis decreases, in parallel with hyper-phosphorylation of the mTOR target S6, and, to a lower extent, of AKT. In nodules derived from primary Ptch1+/−/Tis21KO MBs, treatment with MEN1611, a novel PI3K inhibitor, causes a dramatic reduction of tumor growth, inhibiting proliferation and, conversely, increasing apoptosis, also of tumor CD15+ stem cells, responsible for long-term relapses. Additionally, the phosphorylation of AKT, S6 and 4EBP1 was significantly inhibited, indicating inactivation of the PI3K/AKT/mTOR pathway. Thus, PI3K/AKT/mTOR pathway activation contributes to Ptch1+/−/Tis21KO MB development and to high frequency tumorigenesis, observed when the Tis21 gene is down-regulated. MEN1611 could provide a promising therapy for MB, especially for patient with down-regulation of Btg2 (human ortholog of the murine Tis21 gene), which is frequently deregulated in Shh-type MBs.

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Functional Genomics Identifies Tis21-Dependent Mechanisms and Putative Cancer Drug Targets Underlying Medulloblastoma Shh-Type Development

Cited by 5 publications

References 231 publications

Methylation Profiling of Medulloblastoma in a Clinical Setting Permits Sub-classification and Reveals New Outcome Predictions

Methylation Profiling of Medulloblastoma in a Clinical Setting Permits Sub-classification and Reveals New Outcome Predictions

Suppression of Medulloblastoma Lesions by Forced Migration of Preneoplastic Precursor Cells with Intracerebellar Administration of the Chemokine Cxcl3

Tumor Growth in the High Frequency Medulloblastoma Mouse Model Ptch1+/−/Tis21KO Has a Specific Activation Signature of the PI3K/AKT/mTOR Pathway and Is Counteracted by the PI3K Inhibitor MEN1611

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