ROCK1 mechano-signaling dependency of human malignancies driven by TEAD/YAP activation.
ROCK1 mechano-signaling dependency of human malignancies driven by TEAD/YAP activation.
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DOI：
10.1038/s41467-022-28319-3
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发表时间：
2022-02-04
影响因子：
16.6
通讯作者：
Aaronson SA
中科院分区：
文献类型：
--
作者：
Esposito D;Pant I;Shen Y;Qiao RF;Yang X;Bai Y;Jin J;Poulikakos PI;Aaronson SA
Rho家族通过肌动蛋白细胞骨架的机械信号正向调节生理性的tead/yap转录，而进化保守的河马抑癌途径通过yap胞浆定位/降解来拮抗这种转录。导致这些通路致癌失调的机制，它们在肿瘤中的流行，以及这种失调如何成为治疗靶点，目前还没有解决。我们证明，在人类肿瘤中，p53 DNA接触突变体间接地过度激活RhoA/ROCK1/肌动肌球蛋白信号，这是驱动致癌TEAD/YAP转录的必要条件和充分条件。此外，我们证明河马通路中的复发损伤依赖于致癌基因tead/yap转录的ROCK1/Actomyosin信号的生理水平。最后，我们表明，岩石抑制剂选择性地拮抗人类肿瘤的增殖和运动，无论是哪种机制。因此，我们确定了一种癌症驱动模式和一种精确的医学方法，用于通过上调或依赖内稳态RhoA机械信号的机制来选择性靶向由tead/yap转录驱动的人类恶性肿瘤。P53和河马信号通路之间的串扰在不同的生理环境中已有报道。在这里，作者表明，p53 DNA接触突变间接上调tead/yap转录，并通过过度激活RhoA/ROCK/肌动球蛋白信号来转化细胞。
Rho family mechano-signaling through the actin cytoskeleton positively regulates physiological TEAD/YAP transcription, while the evolutionarily conserved Hippo tumor suppressor pathway antagonizes this transcription through YAP cytoplasmic localization/degradation. The mechanisms responsible for oncogenic dysregulation of these pathways, their prevalence in tumors, as well as how such dysregulation can be therapeutically targeted are not resolved. We demonstrate that p53 DNA contact mutants in human tumors, indirectly hyperactivate RhoA/ROCK1/actomyosin signaling, which is both necessary and sufficient to drive oncogenic TEAD/YAP transcription. Moreover, we demonstrate that recurrent lesions in the Hippo pathway depend on physiological levels of ROCK1/actomyosin signaling for oncogenic TEAD/YAP transcription. Finally, we show that ROCK inhibitors selectively antagonize proliferation and motility of human tumors with either mechanism. Thus, we identify a cancer driver paradigm and a precision medicine approach for selective targeting of human malignancies driven by TEAD/YAP transcription through mechanisms that either upregulate or depend on homeostatic RhoA mechano-signaling. Crosstalk between the p53 and Hippo pathway has been reported in different physiological contexts. Here, the authors show that p53 DNA contact mutations upregulate TEAD/YAP transcription indirectly and transform cells via hyperactivation of RhoA/ROCK/actomyosin signaling.
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影响因子：
64.8
作者：
Chang L;Azzolin L;Di Biagio D;Zanconato F;Battilana G;Lucon Xiccato R;Aragona M;Giulitti S;Panciera T;Gandin A;Sigismondo G;Krijgsveld J;Fassan M;Brusatin G;Cordenonsi M;Piccolo S
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Piccolo S
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Schultz N
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通讯作者：
Kaibuchi, Kozo
影响因子：
7.3
作者：
Feng, Yangbo;LoGrasso, Philip V.;Li, Rongshi
通讯作者：
Li, Rongshi
影响因子：
50.3
作者：
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通讯作者：
Gutkind JS