Opposing Tumor-Promoting and -Suppressive Functions of Rictor/mTORC2 Signaling in Adult Glioma and Pediatric SHH Medulloblastoma

Seçkin Akgül; Yinghua Li; Siyuan Zheng; Marcel Kool; Daniel M. Treisman; Chaoyang Li; Yuan Wang; Susanne Gröbner; Tsuneo Ikenoue; Yiping Shen; Sandra Camelo-Piragua; Gerald Tomasek; Sebastian Stark; Vinay Guduguntla; James F. Gusella; Kun Liang Guan; Stefan M. Pfister; Roel G.W. Verhaak; Yuan Zhu

doi:10.1016/j.celrep.2018.06.050

Opposing Tumor-Promoting and -Suppressive Functions of Rictor/mTORC2 Signaling in Adult Glioma and Pediatric SHH Medulloblastoma

Seçkin Akgül, Yinghua Li, Siyuan Zheng, Marcel Kool, Daniel M. Treisman, Chaoyang Li, Yuan Wang, Susanne Gröbner, Tsuneo Ikenoue, Yiping Shen, Sandra Camelo-Piragua, Gerald Tomasek, Sebastian Stark, Vinay Guduguntla, James F. Gusella, Kun Liang Guan, Stefan M. Pfister, Roel G.W. Verhaak, Yuan Zhu

Onderzoeksoutput: Bijdrage aan tijdschrift › Artikel › peer review

21 Citaten (Scopus)

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Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53 mutant sonic hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively.

Originele taal-2	Engels
Pagina's (van-tot)	463-478.e5
Tijdschrift	Cell Reports
Volume	24
Nummer van het tijdschrift	2
DOI's	https://doi.org/10.1016/j.celrep.2018.06.050
Status	Gepubliceerd - 10 jul. 2018
Extern gepubliceerd	Ja

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10.1016/j.celrep.2018.06.050

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Akgül, S., Li, Y., Zheng, S., Kool, M., Treisman, D. M., Li, C., Wang, Y., Gröbner, S., Ikenoue, T., Shen, Y., Camelo-Piragua, S., Tomasek, G., Stark, S., Guduguntla, V., Gusella, J. F., Guan, K. L., Pfister, S. M., Verhaak, R. G. W., & Zhu, Y. (2018). Opposing Tumor-Promoting and -Suppressive Functions of Rictor/mTORC2 Signaling in Adult Glioma and Pediatric SHH Medulloblastoma. Cell Reports, 24(2), 463-478.e5. https://doi.org/10.1016/j.celrep.2018.06.050

@article{5ee1ca9500e740439423b15da682ffa6,

title = "Opposing Tumor-Promoting and -Suppressive Functions of Rictor/mTORC2 Signaling in Adult Glioma and Pediatric SHH Medulloblastoma",

abstract = "Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53 mutant sonic hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively.",

keywords = "Akt, glioblastoma, mammalian target of rapamycin complex 2, medulloblastoma, mTORC2, p53, phosphatidylinositol 3-kinase pathway, PI3K, Pten, Rictor",

author = "Se{\c c}kin Akg{\"u}l and Yinghua Li and Siyuan Zheng and Marcel Kool and Treisman, {Daniel M.} and Chaoyang Li and Yuan Wang and Susanne Gr{\"o}bner and Tsuneo Ikenoue and Yiping Shen and Sandra Camelo-Piragua and Gerald Tomasek and Sebastian Stark and Vinay Guduguntla and Gusella, {James F.} and Guan, {Kun Liang} and Pfister, {Stefan M.} and Verhaak, {Roel G.W.} and Yuan Zhu",

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s)",

year = "2018",

month = jul,

day = "10",

doi = "10.1016/j.celrep.2018.06.050",

language = "English",

volume = "24",

pages = "463--478.e5",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "2",

}

Akgül, S, Li, Y, Zheng, S, Kool, M, Treisman, DM, Li, C, Wang, Y, Gröbner, S, Ikenoue, T, Shen, Y, Camelo-Piragua, S, Tomasek, G, Stark, S, Guduguntla, V, Gusella, JF, Guan, KL, Pfister, SM, Verhaak, RGW & Zhu, Y 2018, 'Opposing Tumor-Promoting and -Suppressive Functions of Rictor/mTORC2 Signaling in Adult Glioma and Pediatric SHH Medulloblastoma', Cell Reports, vol. 24, nr. 2, blz. 463-478.e5. https://doi.org/10.1016/j.celrep.2018.06.050

TY - JOUR

T1 - Opposing Tumor-Promoting and -Suppressive Functions of Rictor/mTORC2 Signaling in Adult Glioma and Pediatric SHH Medulloblastoma

AU - Akgül, Seçkin

AU - Li, Yinghua

AU - Zheng, Siyuan

AU - Kool, Marcel

AU - Treisman, Daniel M.

AU - Li, Chaoyang

AU - Wang, Yuan

AU - Gröbner, Susanne

AU - Ikenoue, Tsuneo

AU - Shen, Yiping

AU - Camelo-Piragua, Sandra

AU - Tomasek, Gerald

AU - Stark, Sebastian

AU - Guduguntla, Vinay

AU - Gusella, James F.

AU - Guan, Kun Liang

AU - Pfister, Stefan M.

AU - Verhaak, Roel G.W.

AU - Zhu, Yuan

PY - 2018/7/10

Y1 - 2018/7/10

N2 - Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53 mutant sonic hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively.

AB - Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53 mutant sonic hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively.

KW - Akt

KW - glioblastoma

KW - mammalian target of rapamycin complex 2

KW - medulloblastoma

KW - mTORC2

KW - p53

KW - phosphatidylinositol 3-kinase pathway

KW - PI3K

KW - Pten

KW - Rictor

UR - http://www.scopus.com/inward/record.url?scp=85049445040&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2018.06.050

DO - 10.1016/j.celrep.2018.06.050

M3 - Article

C2 - 29996106

AN - SCOPUS:85049445040

SN - 2211-1247

VL - 24

SP - 463-478.e5

JO - Cell Reports

JF - Cell Reports

IS - 2

ER -

Opposing Tumor-Promoting and -Suppressive Functions of Rictor/mTORC2 Signaling in Adult Glioma and Pediatric SHH Medulloblastoma

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