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ROCK1 mechano-signaling dependency of human malignancies driven by TEAD/YAP activation

Author

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  • Davide Esposito

    (Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Ila Pant

    (Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Yao Shen

    (Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Rui F. Qiao

    (Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Xiaobao Yang

    (Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Yiyang Bai

    (Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
    The First Affiliated Hospital of Xi’an Jiaotong University)

  • Jian Jin

    (Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Poulikos I. Poulikakos

    (Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
    The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Stuart A. Aaronson

    (Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

Abstract

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.

Suggested Citation

  • Davide Esposito & Ila Pant & Yao Shen & Rui F. Qiao & Xiaobao Yang & Yiyang Bai & Jian Jin & Poulikos I. Poulikakos & Stuart A. Aaronson, 2022. "ROCK1 mechano-signaling dependency of human malignancies driven by TEAD/YAP activation," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28319-3
    DOI: 10.1038/s41467-022-28319-3
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    References listed on IDEAS

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    1. Gi-Hoon Nam & Eun Jung Lee & Yoon Kyoung Kim & Yeonsun Hong & Yoonjeong Choi & Myung-Jeom Ryu & Jiwan Woo & Yakdol Cho & Dong June Ahn & Yoosoo Yang & Ick-Chan Kwon & Seung-Yoon Park & In-San Kim, 2018. "Combined Rho-kinase inhibition and immunogenic cell death triggers and propagates immunity against cancer," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    2. Lei Chang & Luca Azzolin & Daniele Di Biagio & Francesca Zanconato & Giusy Battilana & Romy Lucon Xiccato & Mariaceleste Aragona & Stefano Giulitti & Tito Panciera & Alessandro Gandin & Gianluca Sigis, 2018. "The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ," Nature, Nature, vol. 563(7730), pages 265-269, November.
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