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ScRNA-seq analysis of SHH medulloblastomas in Gfap-Cre/SmoM2 mice treated with CT-179 or Pox-resiquimod

ABSTRACT: Our parallel studies have shown that the OLIG2 inhibitor CT-179 and the TLR7/8 agonist resiquimod delivered in polyoxazoline nanoparticle (Pox-resiquimod) produce significant anti tumor effects when administered to mice with SHH medulloblastoma. To gain insight into the cellular events set in motion by each treatment, we compared sets of replicate mice with SHH medulloblastomas treated with either CT-179 or POx-resiquimod to a common set of untreated control mice with SHH medulloblastoma.

ORGANISM(S): Mus musculus

PROVIDER: GSE233519 | GEO | 2023/05/30

REPOSITORIES: GEO

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Project description:Medulloblastoma, the most common malignant pediatric brain tumor, is highly heterogeneous with distinct molecular subtypes and cellular origins. Although current treatments improve survival rates, patients suffer severe treatment-related side effects and often relapse of tumors carrying resistance mutations, underscoring an urgent need for alternative targeted therapies. Currently, the genetic alterations underlying this disease are not fully understood. Here we identify GNAS, encoding the G-protein Gs-alpha, as a potent tumor suppressor gene in medulloblastoma. GNAS specifically defines a subset of aggressive Sonic Hedgehog (Shh)-group medulloblastomas. Gnas loss-of-function in distinct lineage progenitors of the developing hindbrain suffices to initiate medulloblastoma. We find that Gs-alpha is highly enriched at primary cilia of granule neuron precursors and suppresses Shh signaling not only by regulating classic cAMP-dependent pathway but also controlling ciliary trafficking of Smoothened. Concurrent cAMP elevation and Smoothened inhibition robustly arrests tumor cell growth in Gnas mutants. We further reveal oligodendrocyte progenitors as a novel cellular origin for anatomically-distinct Shh-associated medulloblastomas. Together, we identify a previously unrecognized tumor suppressor function of Gs-alpha in medulloblastoma partially mediated through inhibiting Shh signaling, and uncover Gs-alpha as a molecular link across disparate cells of origin among Shh-group medulloblastomas, pointing to G- protein modulation as a potential therapeutic avenue. Purpose: To known the gene expression profile of Medulloblastoma which drived by Gnas mutation Methods: mRNAs isolated from the cerebellum of control and Gnas mutants Results:Upregulation of Shh Signaling components in tumors Conclusions: The deletion of Gnas in hGFAP and Olig1 possitive cells result in substantial upregulation of shh signaling and formation of Medulloblastoma cerebellum mRNA profiles of 3 60-day old wild type (Ctrl) and 8 Olig1Cre driven Gsa conditional knockout or 8 hGFAPCre driven conditional knockout mice were generated by deep sequencing using Illumina Hiseq2000

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ScRNA-seq analysis of SHH medulloblastomas in Gfap-Cre/SmoM2 mice treated with CT-179 or Pox-resiquimod

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