Dataset Information

Notch-mediated suppression of multiciliate differentiation promotes choroid plexus tumor initiation from progenitors in response to epithelium-derived Sonic Hedgehog

ABSTRACT: Aberrant Notch signaling has been linked to many cancers including choroid plexus (CP) tumors, a group of rare and predominantly pediatric brain neoplasms. We developed animal models of CP tumors by inducing sustained expression of Notch1 that recapitulate properties of human CP tumors with aberrant NOTCH signaling. Whole transcriptome and functional analyses showed that tumor cell proliferation is associated with Sonic Hedgehog (Shh) in the tumor microenvironment. Unlike CP epithelial cells, which have multiple primary cilia, tumor cells possess a solitary primary cilium as a result of Notch-mediated suppression of multiciliate diffferentiation. A Shh-driven signaling cascade in the primary cilium occurs in tumor cells but not in epithelial cells. Lineage studies show that CP tumors arise from mono-ciliated progenitors in the roof plate characterized by elevated Notch signaling. Abnormal SHH signaling and distinct ciliogenesis are detected in human CP tumors, suggesting SHH pathway and cilia differentiation as potential therapeutic avenues.

ORGANISM(S): Mus musculus

PROVIDER: GSE77123 | GEO | 2016/01/23

SECONDARY ACCESSION(S): PRJNA309500

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

Notch-mediated suppression of multiciliate differentiation promotes choroid plexus tumor initiation from progenitors in response to epithelium-derived Sonic Hedgehog

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets