TY - JOUR
T1 - ROCK1 mechano-signaling dependency of human malignancies driven by TEAD/YAP activation
AU - Esposito, Davide
AU - Pant, Ila
AU - Shen, Yao
AU - Qiao, Rui F.
AU - Yang, Xiaobao
AU - Bai, Yiyang
AU - Jin, Jian
AU - Poulikakos, Poulikos I.
AU - Aaronson, Stuart A.
N1 - Funding Information:
This work was supported by PO1-CA80058 to S.A.A. and funding by the Breast Cancer Research Foundation to S.A.A. and R01GM122749 to J.J. This work was also supported by the Bioinformatics for Next Generation Sequencing (BiNGS) shared resource facility within the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai. The development of this shared resource is partially supported by the NCI P30 Cancer Center support grant.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85124174110&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-28319-3
DO - 10.1038/s41467-022-28319-3
M3 - Article
C2 - 35121738
AN - SCOPUS:85124174110
VL - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 703
ER -