RHOJ Controls EMT-associated Resistance to Chemotherapy

Overview

Journal Nature

Specialty Science

Date 2023 Mar 23

PMID 36949199

Authors

Maud Debaugnies

Sara Rodriguez-Acebes

Jeremy Blondeau

Marie-Astrid Parent

Manuel Zocco

Yura Song

Viviane De Maertelaer

Virginie Moers

Mathilde Latil

Christine Dubois

Katia Coulonval

Francis Impens

Delphi Van Haver

Sara Dufour

Akiyoshi Uemura

Panagiota A Sotiropoulou

Juan Mendez

Cedric Blanpain

Affiliations

Soon will be listed here.

Abstract

The resistance of cancer cells to therapy is responsible for the death of most patients with cancer. Epithelial-to-mesenchymal transition (EMT) has been associated with resistance to therapy in different cancer cells. However, the mechanisms by which EMT mediates resistance to therapy remain poorly understood. Here, using a mouse model of skin squamous cell carcinoma undergoing spontaneous EMT during tumorigenesis, we found that EMT tumour cells are highly resistant to a wide range of anti-cancer therapies both in vivo and in vitro. Using gain and loss of function studies in vitro and in vivo, we found that RHOJ-a small GTPase that is preferentially expressed in EMT cancer cells-controls resistance to therapy. Using genome-wide transcriptomic and proteomic profiling, we found that RHOJ regulates EMT-associated resistance to chemotherapy by enhancing the response to replicative stress and activating the DNA-damage response, enabling tumour cells to rapidly repair DNA lesions induced by chemotherapy. RHOJ interacts with proteins that regulate nuclear actin, and inhibition of actin polymerization sensitizes EMT tumour cells to chemotherapy-induced cell death in a RHOJ-dependent manner. Together, our study uncovers the role and the mechanisms through which RHOJ acts as a key regulator of EMT-associated resistance to chemotherapy.

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