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

He X, Zhang L, Chen Y, Remke M, Shih D, Lu F, Wang H, Deng Y, Yu Y, Xia Y, Wu X, Ramaswamy V, Hu T, Wang F, Zhou W, Burns DK, Kim SH, Kool M, Pfister SM, Weinstein LS, Pomeroy SL, Gilbertson RJ, Rubin JB, Hou Y, Wechsler-Reya R, Taylor MD, Lu QR - Nat. Med. (2014)

Bottom Line: Gαs 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 Gαs 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 Gαs that can be found consistently across Shh-group medulloblastomas of disparate cellular and anatomical origins, highlighting G protein modulation as a potential therapeutic avenue.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Forensic Medicine, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, School of Preclinical and Forensic Medicine, West China Second Hospital, Sichuan University, Chengdu, China. [2] Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

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 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 in mice is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gαs 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 Gαs 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 Gαs that can be found consistently across Shh-group medulloblastomas of disparate cellular and anatomical origins, highlighting G protein modulation as a potential therapeutic avenue.

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GNAS defines a subset of aggressive SHH-group tumors(a-d) MB patients with available survival information and gene expression profiling studies from both Boston and Heidelberg series of MBs 10,11 were divided into two groups using the median GNAS expression value as the cutoff point. The relationship between GNAS mRNA expression and survival time was analyzed according to the Kaplan-Meier method, using log rank statistics. GNAS levels and patient numbers: a, low (n =16), high (n =17); b, low (n = 10), high (n = 10); c, low (n = 32), high (n = 32); d, low (n = 64), high (n = 65).
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Figure 1: GNAS defines a subset of aggressive SHH-group tumors(a-d) MB patients with available survival information and gene expression profiling studies from both Boston and Heidelberg series of MBs 10,11 were divided into two groups using the median GNAS expression value as the cutoff point. The relationship between GNAS mRNA expression and survival time was analyzed according to the Kaplan-Meier method, using log rank statistics. GNAS levels and patient numbers: a, low (n =16), high (n =17); b, low (n = 10), high (n = 10); c, low (n = 32), high (n = 32); d, low (n = 64), high (n = 65).

Mentions: Human MB can be classified into at least four principal subgroups, namely, WNT (Wingless) group, SHH (Sonic hedgehog) group, group 3 and group 4, based on distinct gene expression profiles 1. To define the correlation of GNAS in MB subgroups, we examined GNAS expression from two independent, non-overlapping patient cohorts in the Boston and Heidelberg series 10-12. We found that low GNAS expression was tightly correlated with significantly decreased overall survival within SHH-group tumors (SHH-MB), which comprise approximately 30% of all MBs 1 (Fig. 1a,b). Notably, the prognostic impact of GNAS was not observed in other group tumors and across MB subgroups (Fig. 1c,d; Supplementary Figs. 2,3). These observations suggest that low expression or loss of GNAS specifically defines a subset of aggressive SHH-group MBs.


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

He X, Zhang L, Chen Y, Remke M, Shih D, Lu F, Wang H, Deng Y, Yu Y, Xia Y, Wu X, Ramaswamy V, Hu T, Wang F, Zhou W, Burns DK, Kim SH, Kool M, Pfister SM, Weinstein LS, Pomeroy SL, Gilbertson RJ, Rubin JB, Hou Y, Wechsler-Reya R, Taylor MD, Lu QR - Nat. Med. (2014)

GNAS defines a subset of aggressive SHH-group tumors(a-d) MB patients with available survival information and gene expression profiling studies from both Boston and Heidelberg series of MBs 10,11 were divided into two groups using the median GNAS expression value as the cutoff point. The relationship between GNAS mRNA expression and survival time was analyzed according to the Kaplan-Meier method, using log rank statistics. GNAS levels and patient numbers: a, low (n =16), high (n =17); b, low (n = 10), high (n = 10); c, low (n = 32), high (n = 32); d, low (n = 64), high (n = 65).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4334261&req=5

Figure 1: GNAS defines a subset of aggressive SHH-group tumors(a-d) MB patients with available survival information and gene expression profiling studies from both Boston and Heidelberg series of MBs 10,11 were divided into two groups using the median GNAS expression value as the cutoff point. The relationship between GNAS mRNA expression and survival time was analyzed according to the Kaplan-Meier method, using log rank statistics. GNAS levels and patient numbers: a, low (n =16), high (n =17); b, low (n = 10), high (n = 10); c, low (n = 32), high (n = 32); d, low (n = 64), high (n = 65).
Mentions: Human MB can be classified into at least four principal subgroups, namely, WNT (Wingless) group, SHH (Sonic hedgehog) group, group 3 and group 4, based on distinct gene expression profiles 1. To define the correlation of GNAS in MB subgroups, we examined GNAS expression from two independent, non-overlapping patient cohorts in the Boston and Heidelberg series 10-12. We found that low GNAS expression was tightly correlated with significantly decreased overall survival within SHH-group tumors (SHH-MB), which comprise approximately 30% of all MBs 1 (Fig. 1a,b). Notably, the prognostic impact of GNAS was not observed in other group tumors and across MB subgroups (Fig. 1c,d; Supplementary Figs. 2,3). These observations suggest that low expression or loss of GNAS specifically defines a subset of aggressive SHH-group MBs.

Bottom Line: Gαs 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 Gαs 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 Gαs that can be found consistently across Shh-group medulloblastomas of disparate cellular and anatomical origins, highlighting G protein modulation as a potential therapeutic avenue.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Forensic Medicine, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, School of Preclinical and Forensic Medicine, West China Second Hospital, Sichuan University, Chengdu, China. [2] Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

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 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 in mice is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gαs 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 Gαs 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 Gαs that can be found consistently across Shh-group medulloblastomas of disparate cellular and anatomical origins, highlighting G protein modulation as a potential therapeutic avenue.

Show MeSH
Related in: MedlinePlus