RHOJ controls EMT-associated resistance to chemotherapy

Maud Debaugnies, Sara Rodríguez-Acebes, Jeremy Blondeau, Marie-Astrid Parent, Manuel Zocco, Yura Song, Viviane Maertelaer, Virginie Moers, Mathilde Latil, Christine Dubois, Katia Coulonval, Francis Impens, Delphi Haver, Sara Dufour, Akiyoshi Uemura, Panagiota A. Sotiropoulou, Juan Méndez and Cédric Blanpain ()
Additional contact information
Maud Debaugnies: Université Libre de Buxelles (ULB)
Sara Rodríguez-Acebes: Spanish National Cancer Research Centre
Jeremy Blondeau: Université Libre de Buxelles (ULB)
Marie-Astrid Parent: Université Libre de Buxelles (ULB)
Manuel Zocco: Université Libre de Buxelles (ULB)
Yura Song: Université Libre de Buxelles (ULB)
Viviane Maertelaer: Université Libre de Bruxelles (ULB)
Virginie Moers: Université Libre de Buxelles (ULB)
Mathilde Latil: Université Libre de Buxelles (ULB)
Christine Dubois: Université Libre de Buxelles (ULB)
Katia Coulonval: Université Libre de Bruxelles (ULB)
Francis Impens: Ghent University
Delphi Haver: Ghent University
Sara Dufour: Ghent University
Akiyoshi Uemura: Nagoya City University Graduate School of Medical Sciences
Panagiota A. Sotiropoulou: Université Libre de Buxelles (ULB)
Juan Méndez: Spanish National Cancer Research Centre
Cédric Blanpain: Université Libre de Buxelles (ULB)

Nature, 2023, vol. 616, issue 7955, 168-175

Abstract: Abstract The resistance of cancer cells to therapy is responsible for the death of most patients with cancer1. Epithelial-to-mesenchymal transition (EMT) has been associated with resistance to therapy in different cancer cells2,3. 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.

Date: 2023
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DOI: 10.1038/s41586-023-05838-7

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