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

Davide Esposito,Ila Pant,Jian Jin,Yao Shen,Stuart A Aaronson,Yiyang Bai,Xiaobao Yang,Poulikos I Poulikakos,Rui F Qiao

doi:10.1038/s41467-022-28319-3

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.

Highlights

Rho family mechano-signaling through the actin cytoskeleton positively regulates physiological TEA domain (TEAD)/YAP transcription, while the evolutionarily conserved Hippo tumor suppressor pathway antagonizes this transcription through YAP cytoplasmic localization/degradation
We investigated the gain of function (GOF) mechanism through which certain p53 missense mutants induce the transformed phenotype and identify a paradigm for cancer driver mutations that act indirectly to hyperactivate wild-type RhoA mechano-signaling to levels required for oncogenic TEAD/YAP transcription
Our findings provide proof of concept for the application of ROCK inhibitors, which have been clinically tested in humans for other indications[24], to selectively antagonize the growth and motility of a substantial fraction of human tumors harboring previously untargeted p53 missense or Hippo pathway mutations

Summary

Introduction

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. There remains a critical need to better understand oncogenic mechanisms that have not yet proven amenable to biologically targeted therapies One such mechanism involves the evolutionarily conserved Hippo pathway, which plays an important role in organ size control and normal tissue homeostasis[3] through the actions of its core kinases, MST1/2 and LATS1/2, which negatively regulate TEA domain (TEAD) transcription through phosphorylation and cytosolic retention/ degradation of TEAD co-activators, YAP and TAZ (hereafter designated as YAP)[4]. We investigated the GOF mechanism through which certain p53 missense mutants induce the transformed phenotype and identify a paradigm for cancer driver mutations that act indirectly to hyperactivate wild-type RhoA mechano-signaling to levels required for oncogenic TEAD/YAP transcription. Our findings provide proof of concept for the application of ROCK inhibitors, which have been clinically tested in humans for other indications[24], to selectively antagonize the growth and motility of a substantial fraction of human tumors harboring previously untargeted p53 missense or Hippo pathway mutations

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Results

Conclusion