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

Davide Esposito, Ila Pant, Yao Shen, Rui F. Qiao, Xiaobao Yang, Yiyang Bai, Jian Jin, Poulikos I. Poulikakos and Stuart A. Aaronson ()
Additional contact information
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
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
Stuart A. Aaronson: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-28319-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28319-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-28319-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().