癌症研究
上皮-间质转换
癌变
癌细胞
生物
DNA修复
体内
DNA损伤
化疗
癌症
细胞
转移
DNA
遗传学
作者
Maud Debaugnies,Sara Rodríguez‐Acebes,Jérémy Blondeau,Marie‐Astrid Parent,M.A. 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 Pablo Méndez,Cédric Blanpain
出处
期刊:Nature
[Springer Nature]
日期:2023-03-22
卷期号:616 (7955): 168-175
被引量:24
标识
DOI:10.1038/s41586-023-05838-7
摘要
Abstract The resistance of cancer cells to therapy is responsible for the death of most patients with cancer 1 . Epithelial-to-mesenchymal transition (EMT) has been associated with resistance to therapy in different cancer cells 2,3 . 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.
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