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A mouse model for embryonal tumors with multilayered rosettes uncovers the therapeutic potential of Sonic-hedgehog inhibitors

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A mouse model for embryonal tumors with multilayered rosettes uncovers the therapeutic potential of Sonic-hedgehog inhibitors. / Neumann, Julia E; Wefers, Annika K; Lambo, Sander; Bianchi, Edoardo; Bockstaller, Marie; Dorostkar, Mario M; Meister, Valerie; Schindler, Pia; Korshunov, Andrey; von Hoff, Katja; Nowak, Johannes; Warmuth-Metz, Monika; Schneider, Marlon R; Renner-Müller, Ingrid; Merk, Daniel J; Shakarami, Mehdi; Sharma, Tanvi; Chavez, Lukas; Glass, Rainer; Chan, Jennifer A; Taketo, M Mark; Neumann, Philipp; Kool, Marcel; Schüller, Ulrich.

In: NAT MED, Vol. 23, No. 10, 10.2017, p. 1191-1202.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Neumann, JE, Wefers, AK, Lambo, S, Bianchi, E, Bockstaller, M, Dorostkar, MM, Meister, V, Schindler, P, Korshunov, A, von Hoff, K, Nowak, J, Warmuth-Metz, M, Schneider, MR, Renner-Müller, I, Merk, DJ, Shakarami, M, Sharma, T, Chavez, L, Glass, R, Chan, JA, Taketo, MM, Neumann, P, Kool, M & Schüller, U 2017, 'A mouse model for embryonal tumors with multilayered rosettes uncovers the therapeutic potential of Sonic-hedgehog inhibitors', NAT MED, vol. 23, no. 10, pp. 1191-1202. https://doi.org/10.1038/nm.4402

APA

Neumann, J. E., Wefers, A. K., Lambo, S., Bianchi, E., Bockstaller, M., Dorostkar, M. M., Meister, V., Schindler, P., Korshunov, A., von Hoff, K., Nowak, J., Warmuth-Metz, M., Schneider, M. R., Renner-Müller, I., Merk, D. J., Shakarami, M., Sharma, T., Chavez, L., Glass, R., ... Schüller, U. (2017). A mouse model for embryonal tumors with multilayered rosettes uncovers the therapeutic potential of Sonic-hedgehog inhibitors. NAT MED, 23(10), 1191-1202. https://doi.org/10.1038/nm.4402

Vancouver

Neumann JE, Wefers AK, Lambo S, Bianchi E, Bockstaller M, Dorostkar MM et al. A mouse model for embryonal tumors with multilayered rosettes uncovers the therapeutic potential of Sonic-hedgehog inhibitors. NAT MED. 2017 Oct;23(10):1191-1202. https://doi.org/10.1038/nm.4402

Bibtex

@article{092aefa3f2224b8c816dbcc1b85ffdb9,
title = "A mouse model for embryonal tumors with multilayered rosettes uncovers the therapeutic potential of Sonic-hedgehog inhibitors",
abstract = "Embryonal tumors with multilayered rosettes (ETMRs) have recently been described as a new entity of rare pediatric brain tumors with a fatal outcome. We show here that ETMRs are characterized by a parallel activation of Shh and Wnt signaling. Co-activation of these pathways in mouse neural precursors is sufficient to induce ETMR-like tumors in vivo that resemble their human counterparts on the basis of histology and global gene-expression analyses, and that point to apical radial glia cells as the possible tumor cell of origin. Overexpression of LIN28A, which is a hallmark of human ETMRs, augments Sonic-hedgehog (Shh) and Wnt signaling in these precursor cells through the downregulation of let7-miRNA, and LIN28A/let7a interaction with the Shh pathway was detected at the level of Gli mRNA. Finally, human ETMR cells that were transplanted into immunocompromised host mice were responsive to the SHH inhibitor arsenic trioxide (ATO). Our work provides a novel mouse model in which to study this tumor type, demonstrates the driving role of Wnt and Shh activation in the growth of ETMRs and proposes downstream inhibition of Shh signaling as a therapeutic option for patients with ETMRs.",
keywords = "Journal Article",
author = "Neumann, {Julia E} and Wefers, {Annika K} and Sander Lambo and Edoardo Bianchi and Marie Bockstaller and Dorostkar, {Mario M} and Valerie Meister and Pia Schindler and Andrey Korshunov and {von Hoff}, Katja and Johannes Nowak and Monika Warmuth-Metz and Schneider, {Marlon R} and Ingrid Renner-M{\"u}ller and Merk, {Daniel J} and Mehdi Shakarami and Tanvi Sharma and Lukas Chavez and Rainer Glass and Chan, {Jennifer A} and Taketo, {M Mark} and Philipp Neumann and Marcel Kool and Ulrich Sch{\"u}ller",
year = "2017",
month = oct,
doi = "10.1038/nm.4402",
language = "English",
volume = "23",
pages = "1191--1202",
journal = "NAT MED",
issn = "1078-8956",
publisher = "NATURE PUBLISHING GROUP",
number = "10",

}

RIS

TY - JOUR

T1 - A mouse model for embryonal tumors with multilayered rosettes uncovers the therapeutic potential of Sonic-hedgehog inhibitors

AU - Neumann, Julia E

AU - Wefers, Annika K

AU - Lambo, Sander

AU - Bianchi, Edoardo

AU - Bockstaller, Marie

AU - Dorostkar, Mario M

AU - Meister, Valerie

AU - Schindler, Pia

AU - Korshunov, Andrey

AU - von Hoff, Katja

AU - Nowak, Johannes

AU - Warmuth-Metz, Monika

AU - Schneider, Marlon R

AU - Renner-Müller, Ingrid

AU - Merk, Daniel J

AU - Shakarami, Mehdi

AU - Sharma, Tanvi

AU - Chavez, Lukas

AU - Glass, Rainer

AU - Chan, Jennifer A

AU - Taketo, M Mark

AU - Neumann, Philipp

AU - Kool, Marcel

AU - Schüller, Ulrich

PY - 2017/10

Y1 - 2017/10

N2 - Embryonal tumors with multilayered rosettes (ETMRs) have recently been described as a new entity of rare pediatric brain tumors with a fatal outcome. We show here that ETMRs are characterized by a parallel activation of Shh and Wnt signaling. Co-activation of these pathways in mouse neural precursors is sufficient to induce ETMR-like tumors in vivo that resemble their human counterparts on the basis of histology and global gene-expression analyses, and that point to apical radial glia cells as the possible tumor cell of origin. Overexpression of LIN28A, which is a hallmark of human ETMRs, augments Sonic-hedgehog (Shh) and Wnt signaling in these precursor cells through the downregulation of let7-miRNA, and LIN28A/let7a interaction with the Shh pathway was detected at the level of Gli mRNA. Finally, human ETMR cells that were transplanted into immunocompromised host mice were responsive to the SHH inhibitor arsenic trioxide (ATO). Our work provides a novel mouse model in which to study this tumor type, demonstrates the driving role of Wnt and Shh activation in the growth of ETMRs and proposes downstream inhibition of Shh signaling as a therapeutic option for patients with ETMRs.

AB - Embryonal tumors with multilayered rosettes (ETMRs) have recently been described as a new entity of rare pediatric brain tumors with a fatal outcome. We show here that ETMRs are characterized by a parallel activation of Shh and Wnt signaling. Co-activation of these pathways in mouse neural precursors is sufficient to induce ETMR-like tumors in vivo that resemble their human counterparts on the basis of histology and global gene-expression analyses, and that point to apical radial glia cells as the possible tumor cell of origin. Overexpression of LIN28A, which is a hallmark of human ETMRs, augments Sonic-hedgehog (Shh) and Wnt signaling in these precursor cells through the downregulation of let7-miRNA, and LIN28A/let7a interaction with the Shh pathway was detected at the level of Gli mRNA. Finally, human ETMR cells that were transplanted into immunocompromised host mice were responsive to the SHH inhibitor arsenic trioxide (ATO). Our work provides a novel mouse model in which to study this tumor type, demonstrates the driving role of Wnt and Shh activation in the growth of ETMRs and proposes downstream inhibition of Shh signaling as a therapeutic option for patients with ETMRs.

KW - Journal Article

U2 - 10.1038/nm.4402

DO - 10.1038/nm.4402

M3 - SCORING: Journal article

C2 - 28892064

VL - 23

SP - 1191

EP - 1202

JO - NAT MED

JF - NAT MED

SN - 1078-8956

IS - 10

ER -