YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis

Kristian W. Pajtler, Yiju Wei, Konstantin Okonechnikov, Patricia B. G. Silva, Mikaella Vouri, Lei Zhang, Sebastian Brabetz, Laura Sieber, Melissa Gulley, Monika Mauermann, Tatjana Wedig, Norman Mack, Yuka Imamura Kawasawa, Tanvi Sharma, Marc Zuckermann, Felipe Andreiuolo, Eric Holland, Kendra Maass, Huiqin Körkel-Qu, Hai-Kun Liu, Felix Sahm, David Capper, Jens Bunt, Linda J. Richards, David T. W. Jones, Andrey Korshunov, Lukas Chavez, Peter Lichter, Mikio Hoshino, Stefan M. Pfister, Marcel Kool, Wei Li () and Daisuke Kawauchi ()
Additional contact information
Kristian W. Pajtler: Hopp-Children’s Cancer Center Heidelberg (KiTZ)
Yiju Wei: Penn State College of Medicine
Konstantin Okonechnikov: Hopp-Children’s Cancer Center Heidelberg (KiTZ)
Patricia B. G. Silva: Hopp-Children’s Cancer Center Heidelberg (KiTZ)
Mikaella Vouri: Hopp-Children’s Cancer Center Heidelberg (KiTZ)
Lei Zhang: Penn State College of Medicine
Sebastian Brabetz: Hopp-Children’s Cancer Center Heidelberg (KiTZ)
Laura Sieber: Hopp-Children’s Cancer Center Heidelberg (KiTZ)
Melissa Gulley: Penn State College of Medicine
Monika Mauermann: Hopp-Children’s Cancer Center Heidelberg (KiTZ)
Tatjana Wedig: Hopp-Children’s Cancer Center Heidelberg (KiTZ)
Norman Mack: Hopp-Children’s Cancer Center Heidelberg (KiTZ)
Yuka Imamura Kawasawa: Penn State College of Medicine
Tanvi Sharma: Hopp-Children’s Cancer Center Heidelberg (KiTZ)
Marc Zuckermann: Hopp-Children’s Cancer Center Heidelberg (KiTZ)
Felipe Andreiuolo: Ste. Anne Hospital
Eric Holland: Fred Hutchinson Cancer Research Center
Kendra Maass: Hopp-Children’s Cancer Center Heidelberg (KiTZ)
Huiqin Körkel-Qu: German Cancer Research Center (DKFZ)
Hai-Kun Liu: German Cancer Research Center (DKFZ)
Felix Sahm: German Cancer Research Center (DKFZ)
David Capper: German Cancer Research Center (DKFZ)
Jens Bunt: The University of Queensland
Linda J. Richards: The University of Queensland
David T. W. Jones: Hopp-Children’s Cancer Center Heidelberg (KiTZ)
Andrey Korshunov: German Cancer Research Center (DKFZ)
Lukas Chavez: Hopp-Children’s Cancer Center Heidelberg (KiTZ)
Peter Lichter: German Cancer Research Center (DKFZ)
Mikio Hoshino: National Institute of Neuroscience, NCNP
Stefan M. Pfister: Hopp-Children’s Cancer Center Heidelberg (KiTZ)
Marcel Kool: Hopp-Children’s Cancer Center Heidelberg (KiTZ)
Wei Li: Penn State College of Medicine
Daisuke Kawauchi: Hopp-Children’s Cancer Center Heidelberg (KiTZ)

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions are sufficient to drive malignant transformation in mice, and the resulting tumors share histo-molecular characteristics of human ependymomas. Nuclear localization of YAP1-MAMLD1 protein is mediated by MAMLD1 and independent of YAP1-Ser127 phosphorylation. Chromatin immunoprecipitation-sequencing analyses of human YAP1-MAMLD1-positive ependymoma reveal enrichment of NFI and TEAD transcription factor binding site motifs in YAP1-bound regulatory elements, suggesting a role for these transcription factors in YAP1-MAMLD1-driven tumorigenesis. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumor induction in mice. Together, these results demonstrate that the YAP1-MAMLD1 fusion functions as an oncogenic driver of ependymoma through recruitment of TEADs and NFIs, indicating a rationale for preclinical studies to block the interaction between YAP1 fusions and NFI and TEAD transcription factors.

Date: 2019
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DOI: 10.1038/s41467-019-11884-5

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