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Title: The G-protein Alpha Subunit Gsα Is A Tumor Suppressor In Sonic Hedgehog-driven Medulloblastoma [Copy number analysis]      
dateReleased:
08-24-2014
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. We isolated genomic DNAs from the cerebellum of adult wildtype mice and tumor tissue from individual GFAP-Gnas or Olig1-Gnas mutants and performed the Copy number variation analysis.
privacy:
not applicable
aggregation:
instance of dataset
ID:
E-GEOD-60416
refinement:
raw
alternateIdentifiers:
60416
keywords:
functional genomics
dateModified:
09-01-2014
creators:
Richard Lu
availability:
available
types:
gene expression
name:
Mus musculus
ID:
A-GEOD-10989
name:
NimbleGen Mouse CGH 3x720K Whole-Genome Tiling Array (Build MM9)
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-60416/E-GEOD-60416.raw.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-60416/E-GEOD-60416.processed.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE60416
storedIn:
Gene Expression Omnibus
qualifier:
not compressed
format:
HTML
accessType:
landing page
primary:
true
authentication:
none
authorization:
none
abbreviation:
EBI
homePage: http://www.ebi.ac.uk/
ID:
SCR:004727
name:
European Bioinformatics Institute
homePage: https://www.ebi.ac.uk/arrayexpress/
ID:
SCR:002964
name:
ArrayExpress

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