Journal Article

DKFZ-2017-05190

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A mouse model for embryonal tumors with multilayered rosettes uncovers the therapeutic potential of Sonic-hedgehog inhibitors.

Neumann, J. E. ; Wefers, A. K.DKFZ* ; Lambo, S.DKFZ* ; Bianchi, E. ; Bockstaller, M. ; Dorostkar, M. M. ; Meister, V. ; Schindler, P. ; Korshunov, A.DKFZ* ; von Hoff, K. ; Nowak, J. ; Warmuth-Metz, M. ; Schneider, M. R. ; Renner-Müller, I. ; Merk, D. J. ; Shakarami, M. ; Sharma, T.DKFZ* ; Chavez, L.DKFZ* ; Glass, R. ; Chan, J. A. ; Taketo, M. M. ; Neumann, P. ; Kool, M.DKFZ* ; Schüller, U.

2017
Nature America Inc. New York, NY

This record in other databases:  

Please use a persistent id in citations: doi:10.1038/nm.4402

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.

Keyword(s): Antineoplastic Agents ; Arsenicals ; Gli protein, mouse ; Hedgehog Proteins ; Lin-28 protein, mouse ; MicroRNAs ; Oxides ; RNA-Binding Proteins ; Shh protein, mouse ; Zinc Finger Protein GLI1 ; mirnlet7 microRNA, mouse ; arsenic trioxide

---

Contributing Institute(s):

1. Pädiatrische Neuroonkologie (B062)
2. KKE Neuropathologie (G380)
3. DKTK Heidelberg (L101)
4. DKTK München (L701)

Research Program(s):

1. 319H - Addenda (POF3-319H) (POF3-319H)

Appears in the scientific report 2017

---

Database coverage:
; BIOSIS Previews ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 30 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

---