Oncogenic Amplification of Zygotic Dux Factors in Regenerating p53-Deficient Muscle Stem Cells Defines a Molecular Cancer Subtype
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Oncogenic Amplification of Zygotic Dux Factors in Regenerating p53-Deficient Muscle Stem Cells Defines a Molecular Cancer Subtype. / Preussner, Jens; Zhong, Jiasheng; Sreenivasan, Krishnamoorthy; Günther, Stefan; Engleitner, Thomas; Künne, Carsten; Glatzel, Markus; Rad, Roland; Looso, Mario; Braun, Thomas; Kim, Johnny.
in: CELL STEM CELL, Jahrgang 23, Nr. 6, 06.12.2018, S. 794-805.e4.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Oncogenic Amplification of Zygotic Dux Factors in Regenerating p53-Deficient Muscle Stem Cells Defines a Molecular Cancer Subtype
AU - Preussner, Jens
AU - Zhong, Jiasheng
AU - Sreenivasan, Krishnamoorthy
AU - Günther, Stefan
AU - Engleitner, Thomas
AU - Künne, Carsten
AU - Glatzel, Markus
AU - Rad, Roland
AU - Looso, Mario
AU - Braun, Thomas
AU - Kim, Johnny
N1 - Copyright © 2018 Elsevier Inc. All rights reserved.
PY - 2018/12/6
Y1 - 2018/12/6
N2 - The identity of tumor-initiating cells in many cancer types is unknown. Tumors often express genes associated with embryonic development, although the contributions of zygotic programs to tumor initiation and formation are poorly understood. Here, we show that regeneration-induced loss of quiescence in p53-deficient muscle stem cells (MuSCs) results in rhabdomyosarcoma formation with 100% penetrance. Genomic analyses of purified tumor cells revealed spontaneous and discrete oncogenic amplifications in MuSCs that drive tumorigenesis, including, but not limited to, the amplification of the cleavage-stage Dux transcription factor (TF) Duxbl. We further found that Dux factors drive an early embryonic gene signature that defines a molecular subtype across a broad range of human cancers. Duxbl initiates tumorigenesis by enforcing a mesenchymal-to-epithelial transition, and targeted inactivation of Duxbl specifically in Duxbl-expressing tumor cells abolishes their expansion. These findings reveal how regeneration and genomic instability can interact to activate zygotic genes that drive tumor initiation and growth.
AB - The identity of tumor-initiating cells in many cancer types is unknown. Tumors often express genes associated with embryonic development, although the contributions of zygotic programs to tumor initiation and formation are poorly understood. Here, we show that regeneration-induced loss of quiescence in p53-deficient muscle stem cells (MuSCs) results in rhabdomyosarcoma formation with 100% penetrance. Genomic analyses of purified tumor cells revealed spontaneous and discrete oncogenic amplifications in MuSCs that drive tumorigenesis, including, but not limited to, the amplification of the cleavage-stage Dux transcription factor (TF) Duxbl. We further found that Dux factors drive an early embryonic gene signature that defines a molecular subtype across a broad range of human cancers. Duxbl initiates tumorigenesis by enforcing a mesenchymal-to-epithelial transition, and targeted inactivation of Duxbl specifically in Duxbl-expressing tumor cells abolishes their expansion. These findings reveal how regeneration and genomic instability can interact to activate zygotic genes that drive tumor initiation and growth.
KW - Journal Article
U2 - 10.1016/j.stem.2018.10.011
DO - 10.1016/j.stem.2018.10.011
M3 - SCORING: Journal article
C2 - 30449715
VL - 23
SP - 794-805.e4
JO - CELL STEM CELL
JF - CELL STEM CELL
SN - 1934-5909
IS - 6
ER -
