MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
Nat Cancer. 2022 Sep;3(9):1105-1122. doi: 10.1038/s43018-022-00408-8. Epub 2022 Aug 1.
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.
弥漫性内生脑桥胶质瘤（DIPG）最致命的亚型是 H3K27M。虽然 ACVR1 突变已被牵涉到这种目前无法治愈的疾病的发病机制中，但骨形态发生蛋白（BMP）信号对超过 60%携带 ACVR1 野生型的 H3K27M DIPG 的影响仍不清楚。在这里，我们表明 BMP 配体以 SMAD 依赖性的方式对 H3.3K27M 和 ACVR1 WT DIPG 发挥强大的肿瘤抑制作用。具体来说，临床数据显示，许多 DIPG 肿瘤已经利用了 CHRDL1 来劫持 BMP 配体的能力。我们发现，BMP 信号的激活通过表观遗传调控 CXXC5 促进 DIPG 肿瘤细胞从“长期干细胞样”状态退出分化，CXXC5 作为肿瘤抑制因子和 BMP 信号的正调节剂。除了显示 BMP 信号如何影响 DIPG 之外，我们的研究还确定了 Dacinostat 对 DIPG 的强大抗肿瘤功效。因此，我们的研究描绘了 BMP 信号通路在 DIPG 亚型中的上下文相关特征。
