Muscle Stem Cells Give Rise to Rhabdomyosarcomas in a Severe Mouse Model of Duchenne Muscular Dystrophy

Most human cancers originate from high-turnover tissues, while low-proliferating tissues, like skeletal muscle, exhibit a lower incidence of tumor development. In Duchenne muscular dystrophy (DMD), which induces increased skeletal muscle regeneration, tumor incidence is increased. Rhabdomyosarcomas...

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Bibliographic Details
Published in:Cell reports (Cambridge) 2019-01, Vol.26 (3), p.689-701.e6
Main Authors: Boscolo Sesillo, Francesca, Fox, David, Sacco, Alessandra
Format: Article
Language:English
Subjects:
Animals
cancer
Disease Models, Animal
Mice
muscle stem cells
Muscle, Skeletal - metabolism
muscular dystrophy
Muscular Dystrophy, Duchenne - complications
Muscular Dystrophy, Duchenne - pathology
rhabdomyosarcoma
Rhabdomyosarcoma - etiology
Rhabdomyosarcoma - pathology
self-renewal
skeletal muscle
Stem Cells - metabolism
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Summary:Most human cancers originate from high-turnover tissues, while low-proliferating tissues, like skeletal muscle, exhibit a lower incidence of tumor development. In Duchenne muscular dystrophy (DMD), which induces increased skeletal muscle regeneration, tumor incidence is increased. Rhabdomyosarcomas (RMSs), a rare and aggressive type of soft tissue sarcoma, can develop in this context, but the impact of DMD severity on RMS development and its cell of origin are poorly understood. Here, we show that RMS latency is affected by DMD severity and that muscle stem cells (MuSCs) can give rise to RMS in dystrophic mice. We report that even before tumor formation, MuSCs exhibit increased self-renewal and an expression signature associated with RMSs. These cells can form tumorspheres in vitro and give rise to RMSs in vivo. Finally, we show that the inflammatory genes Ccl11 and Rgs5 are involved in RMS growth. Together, our results show that DMD severity drives MuSC-mediated RMS development. [Display omitted] •Dystrophic disease progression accelerates rhabdomyosarcoma (RMS) formation•MuSCs carry a gene signature characteristic of RMSs before tumor formation•Increased self-renewal contributes to dystrophic MuSCs transformation•Dystrophic MuSCs induce the development of RMS in vivo Boscolo Sesillo et al. describe how Duchenne muscular dystrophy severity increases rhabdomyosarcoma (RMS) formation and reduces latency. This study shows that muscle stem cells give rise to tumorspheres in vitro and RMS tumors in vivo and identify genes involved in RMS growth.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2018.12.089