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The G protein ? subunit G?s is a tumor suppressor in Sonic hedgehog-driven medulloblastoma.

ABSTRACT: Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Herein, we identify GNAS, encoding the G protein G?s, as a potent tumor suppressor gene that, when expressed at low levels, defines a subset of aggressive Sonic hedgehog (SHH)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically distinct progenitors in mice is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. G?s is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation in levels of a G?s effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas-ablated mice. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for G?s that can be found consistently across Shh-group medulloblastomas of disparate cellular and anatomical origins, highlighting G protein modulation as a potential therapeutic avenue.

SUBMITTER: He X

PROVIDER: S-EPMC4334261 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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The G protein α subunit Gαs is a tumor suppressor in Sonic hedgehog-driven medulloblastoma.

He Xuelian X Zhang Liguo L Chen Ying Y Remke Marc M Shih David D Lu Fanghui F Wang Haibo H Deng Yaqi Y Yu Yang Y Xia Yong Y Wu Xiaochong X Ramaswamy Vijay V Hu Tom T Wang Fan F Zhou Wenhao W Burns Dennis K DK Kim Se Hoon SH Kool Marcel M Pfister Stefan M SM Weinstein Lee S LS Pomeroy Scott L SL Gilbertson Richard J RJ Rubin Joshua B JB Hou Yiping Y Wechsler-Reya Robert R Taylor Michael D MD Lu Q Richard QR

Nature medicine 20140824 9

Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Herein, we identify GNAS, encoding the G protein Gαs, as a potent tumor suppressor gene that, when expressed at low levels, defines a subset of aggressive Sonic hedgehog (SHH)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically distinct progenitors i ...[more]

PMID: 25150496

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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

Dataset Information

The G protein ? subunit G?s is a tumor suppressor in Sonic hedgehog-driven medulloblastoma.

Publications

The G protein α subunit Gαs is a tumor suppressor in Sonic hedgehog-driven medulloblastoma.

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