Sanghrajka Reeti Mayur, Koche Richard, Medrano Hector, El Nagar Salsabiel, Stephen Daniel N, Lao Zhimin, Bayin N Sumru, Ge Kai, Joyner Alexandra L
Developmental Biology Program, Sloan Kettering Institute of Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Biochemistry, Cell and Molecular Biology Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
iScience. 2023 Sep 9;26(10):107831. doi: 10.1016/j.isci.2023.107831. eCollection 2023 Oct 20.
The major cause of treatment failure and mortality among medulloblastoma patients is metastasis intracranially or along the spinal cord. The molecular mechanisms driving tumor metastasis in Sonic hedgehog-driven medulloblastoma (SHH-MB) patients, however, remain largely unknown. In this study we define a tumor suppressive role of (), a gene frequently mutated in the most metastatic β-subtype. Strikingly, genetic mouse models of SHH-MB demonstrate that heterozygous loss of in conjunction with activation of the SHH pathway causes highly penetrant disease with decreased survival, increased hindbrain invasion and spinal cord metastasis. Loss of attenuates neural differentiation and shifts the transcriptional/chromatin landscape of primary and metastatic tumors toward a decrease in differentiation genes and tumor suppressors and an increase in genes/pathways implicated in advanced stage cancer and metastasis (TGFβ, Notch, , , and ). Thus, secondary heterozygous mutations likely have prognostic value for identifying SHH-MB patients prone to develop metastasis.
髓母细胞瘤患者治疗失败和死亡的主要原因是颅内或沿脊髓转移。然而，在 Sonic 刺猬因子驱动的髓母细胞瘤（SHH-MB）患者中，驱动肿瘤转移的分子机制在很大程度上仍不清楚。在本研究中，我们定义了（）的肿瘤抑制作用，（）是在最具转移性的β亚型中经常发生突变的一个基因。引人注目的是，SHH-MB 的基因小鼠模型表明，（）的杂合缺失与 SHH 通路的激活相结合会导致高侵袭性疾病，生存率降低，后脑侵袭增加和脊髓转移。（）的缺失减弱了神经分化，并使原发性和转移性肿瘤的转录/染色质格局朝着分化基因和肿瘤抑制因子减少以及与晚期癌症和转移相关的基因/通路（TGFβ、Notch、（）、（）和（））增加的方向转变。因此，继发性杂合（）突变可能对识别易于发生转移的 SHH-MB 患者具有预后价值。
