Context-dependent tumor-suppressive BMP signaling in diffuse intrinsic pontine glioma regulates stemness through epigenetic regulation of CXXC5
The most lethal subtype of diffuse intrinsic pontine glioma (DIPG) is H3K27M. Although ACVR1 mutations have been implicated in the pathogenesis of this currently incurable disease, the impacts of bone morphogenetic protein (BMP) signaling on more than 60% of H3K27M DIPG carrying ACVR1 wild-type rema...
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Veröffentlicht in: | Nature cancer 2022-09, Vol.3 (9), p.1105-1122 |
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Zusammenfassung: | The most lethal subtype of diffuse intrinsic pontine glioma (DIPG) is H3K27M. Although
ACVR1
mutations have been implicated in the pathogenesis of this currently incurable disease, the impacts of bone morphogenetic protein (BMP) signaling on more than 60% of H3K27M DIPG carrying
ACVR1
wild-type remain unknown. Here we show that BMP ligands exert potent tumor-suppressive effects against H3.3K27M and ACVR1 WT DIPG in a SMAD-dependent manner. Specifically, clinical data revealed that many DIPG tumors have exploited the capacity of CHRDL1 to hijack BMP ligands. We discovered that activation of BMP signaling promotes the exit of DIPG tumor cells from ‘prolonged stem-cell-like’ state to differentiation by epigenetically regulating CXXC5, which acts as a tumor suppressor and positive regulator of BMP signaling. Beyond showing how BMP signaling impacts DIPG, our study also identified the potent antitumor efficacy of Dacinostat for DIPG. Thus, our study delineates context-dependent features of the BMP signaling pathway in a DIPG subtype.
Xi and colleagues show that BMP signaling has tumor-suppressive effects in
ACVR1
wild-type diffuse intrinsic pontine glioma by modulating stemness via chromatin regulation of
CXXC5
, and demonstrate the therapeutic potential of this pathway using in vivo mouse models. |
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ISSN: | 2662-1347 2662-1347 |
DOI: | 10.1038/s43018-022-00408-8 |