Dual Pten/Tp53 Suppression Promotes Sarcoma Progression by Activating Notch Signaling
Dual Pten/Tp53 Suppression Promotes Sarcoma Progression by Activating Notch Signaling
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DOI：
10.1016/j.ajpath.2013.02.035
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发表时间：
2013-06-01
影响因子：
6
通讯作者：
Hernando, Eva
中科院分区：
文献类型：
--
作者：
Guijarro, Maria V.;Dahiya, Sonika;Hernando, Eva
软组织肉瘤是一组异质性肿瘤，临床预后较差。尽管软组织肉瘤的一部分以简单的核型和反复的染色体易位为特征，但导致细胞遗传学复杂的肉瘤的机制在很大程度上是未知的。临床证据导致我们部分失活了小鼠平滑肌谱系中的Pten和TP53，这些小鼠发展成高度未分化的多形性肉瘤、平滑肌肉瘤和癌肉瘤，这些肿瘤广泛地概括了人类疾病，包括异常的核型和转移行为。发现PTEN单倍体缺失，而TP53的野生型等位基因总是获得点突变。基因表达谱显示，与Pten(+/+)TP53(Delta+)肿瘤相比，在Pten(Delta/+)TP53(Delta+)肿瘤中Notch信号上调。一直以来，Pten沉默加剧了TP53缺陷的小鼠骨髓间充质干细胞和肿瘤细胞的克隆形成和侵袭潜能，并激活了Notch途径。此外，Pten(Delta/+)TP53(Delta+)和shPten转导的Pten(+/+)TP53(Delta+)肿瘤细胞的致癌行为增加可以被γ-分泌酶抑制剂处理所抵消，这表明这些肿瘤的侵袭性至少部分可以归因于增强的Notch信号。这项研究证明了Pten和TP53抑制在复杂核型肉瘤中的协同作用，同时建立了Notch作为一个重要的功能参与者，在肿瘤进展过程中这些通路的串扰中。我们的结果强调了对高度恶性肉瘤患者进行分子分类以进行靶向治疗的重要性。
Softtissue sarcomas are a heterogeneous group of tumors associated with poor clinical outcome. Although a subset of soft tissue sarcomas is characterized by simple karyotypes and recurrent chromosomal translocations, the mechanisms driving cytogenetically complex sarcomas are largely unknown. Clinical evidence led us to partially inactivate Pten and Tp53 in the smooth muscle lineage of mice, which developed high-grade undifferentiated pLeomorphic sarcomas, leiomyosarcomas, and carcinosarcomas that widely recapitulate the human disease, including the aberrant karyotype and metastatic behavior. Pten was found haploinsufficient, whereas the wild-type allele of Tp53 invariably gained point mutations. Gene expression profiles showed up-regulated Notch signaling in Pten (Delta/+)Tp53(Delta+) tumors compared with Pten (+/+)Tp53(Delta+) tumors. Consistently, Pten silencing exacerbated the clonogenic and invasive potential of Tp53-deficient bone marrow derived mouse mesenchymal stem cells and tumor cells and activated the Notch pathway. Moreover, the increased oncogenic behavior of Pten (Delta/+)Tp53(Delta+) and shPten-transduced Pten (+/+)Tp53(Delta+) tumor cells was counteracted by treatment with a y-secretase inhibitor, suggesting that the aggressiveness of those tumors can be attributed, at least in part, to enhanced Notch signaling. This study demonstrates a cooperative role for Pten and Tp53 suppression in complex karyotype sarcomas while establishing Notch as an important functional player in the cross talk of these pathways during tumor progression. Our results highlight the importance of molecularly subclassifying patients with highgrade sarcoma for targeted treatments.