Loss of MST/Hippo Signaling in a Genetically Engineered Mouse Model of Fusion-Positive Rhabdomyosarcoma Accelerates Tumorigenesis.
Loss of MST/Hippo Signaling in a Genetically Engineered Mouse Model of Fusion-Positive Rhabdomyosarcoma Accelerates Tumorigenesis.
复制标题
融合阳性横纹肌肉瘤基因工程小鼠模型中 MST/Hippo 信号传导的缺失会加速肿瘤发生。
DOI：
10.1158/0008-5472.can-17-3912
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发表时间：
2018
期刊：
影响因子：
11.2
通讯作者：
Linardic,CorinneM
中科院分区：
文献类型：
--
作者：
Oristian,KristianneM;Crose,LisaES;Kuprasertkul,Nina;Bentley,RexC;Lin,Yi-Tzu;Williams,Nerissa;Kirsch,DavidG;Linardic,CorinneM
融合阳性的肺泡型横纹肌肉瘤(ARMS)的一个特征是存在编码PAX3-FOX01融合癌基因的染色体易位。初步的基于细胞的模拟实验表明，PAX3-FOXO1是必要的，但不足以促进手臂肿瘤的发生，这表明需要更多的分子改变来启动和维持肿瘤的生长。以前，我们发现PAX3-FOXO1阳性的ARM受到HIPPO信号通路失调的促进，表现为YAP1表达增加和MST活性降低。我们假设，在ARM的基因工程小鼠模型(GEMM)中，去除MST/Hippo信号会加速肿瘤的发生。为此，将MST1/2-FLOXED(Stk3F/F；Stk4F/F)小鼠与先前建立的手臂GEMM杂交，该GEMM是由内源性Pax3基因座的Pax3：Foxo1的条件表达和表达CDKn2的Myf6(肌源性因子6)细胞的条件性丢失驱动的。与Pax3PF/PF、CDKn2aF/F、Myf6ICN/+对照组相比，Stk3F/F；Stk4F/F；Pax3PF/PF；Cdkn2aF/F；Myf6ICN/+animals组肿瘤形成速度加快(P<；0.0001)，肿瘤外显率增加(88%比27%)。GEMM肿瘤的组织学特征与上肢一致。GEMM肿瘤细胞系表现为增殖和侵袭增加，衰老和肌源性分化减少。这些数据表明，MST/Hippo信号的丢失与Pax3：Foxo1的表达和CDK2的丢失共同促进肿瘤的发生。在这个模型中，肿瘤发生的快速开始和增加的外显性为询问武器生物学和筛选新的治疗方法提供了一个强大的工具。意义：一个新的小鼠模型揭示了HIPPO/MST下调在PAX3-FOXO1阳性横纹肌肉瘤发生中的关键作用。癌症资源；78(19)；5513-20。
A hallmark of fusion-positive alveolar rhabdomyosarcoma (aRMS) is the presence of a chromosomal translocation encoding thePAX3–FOXO1fusion oncogene. Primary cell-based modeling experiments have shown thatPAX3–FOXO1is necessary, but not sufficient for aRMS tumorigenesis, indicating additional molecular alterations are required to initiate and sustain tumor growth. Previously, we showed thatPAX3–FOXO1-positive aRMS is promoted by dysregulated Hippo pathway signaling, as demonstrated by increased YAP1 expression and decreased MST activity. We hypothesized that ablating MST/Hippo signaling in a genetically engineered mouse model (GEMM) of aRMS would accelerate tumorigenesis. To this end, MST1/2-floxed (Stk3F/F;Stk4F/F) mice were crossed with a previously established aRMS GEMM driven by conditional expression ofPax3:Foxo1from the endogenousPax3locus and conditional loss ofCdkn2ainMyf6(myogenic factor 6)-expressing cells. Compared withPax3PF/PF;Cdkn2aF/F;Myf6ICN/+controls,Stk3F/F;Stk4F/F;Pax3PF/PF;Cdkn2aF/F;Myf6ICN/+animals displayed accelerated tumorigenesis (P< 0.0001) and increased tumor penetrance (88% vs. 27%). GEMM tumors were histologically consistent with aRMS. GEMM tumor-derived cell lines showed increased proliferation and invasion and decreased senescence and myogenic differentiation. These data suggest that loss of MST/Hippo signaling acts withPax3:Foxo1expression andCdkn2aloss to promote tumorigenesis. The rapid onset and increased penetrance of tumorigenesis in this model provide a powerful tool for interrogating aRMS biology and screening novel therapeutics.Significance:A novel mouse model sheds light on the critical role of Hippo/MST downregulation in PAX3-FOXO1–positive rhabdomyosarcoma tumorigenesis.Cancer Res; 78(19); 5513–20. ©2018 AACR.
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影响因子：
7.7
作者：
Tenente, Ines M.;Hayes, Madeline N.;Langenau, David M.
通讯作者：
Langenau, David M.
影响因子：
13.8
作者：
Park, Hyun Woo;Guan, Kun-Liang
通讯作者：
Guan, Kun-Liang
影响因子：
0.9
作者：
Chatopadhayay, Rahul;Tiwari, Preeti;Pandey, Vaibhav
通讯作者：
Pandey, Vaibhav
影响因子：
2.9
作者：
Galan JA;Avruch J
通讯作者：
Avruch J
DOI：
10.1016/j.bbalip.2006.01.006
发表时间：
2006-01-01
影响因子：
4.8
作者：
Becciolini, L;Meacci, E;Bruni, P
通讯作者：
Bruni, P