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, Jahrgang 23, Nr. 10, 10.2017, S. 1191-1202.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -