Epithelial-to-mesenchymal transition (EMT) controls resistance to cancer therapies both in vitro and in vivo but the precise mechanisms behind this phenomenon in vivo are less clear. Now, Blan-pain and colleagues provide evidence that the small RHO GTPase, RHOJ, mediates resistance to chemotherapy in tumour cells that have undergone EMT. Using a genetically engineered mouse model (GEMM) of skin squamous cell carcinoma (SCC), Debaugnies et al. observed that 32 of SCCs failed to respond to a combination of two chemotherapeutic drugs, cisplatin and 5-fluorouracil (5FU). In searching for a potential regulator of this resistance, the researchers noted that RHOJ was more highly expressed in EMT-associated tumour cells. Furthermore, knocking out Rhoj in their GEMM led to elevated cell death of EMT-associated tumour cells upon treatment with cisplatin and 5-FU. In a series of experiments unravelling the mechanism of action, it was shown that RHOJ could control nuclear actin polymerization in line with its established role in coordinating actin dynamics. This activity, in turn, allows EMT-associated cells to tolerate replicative stress by promoting the repair of DNA damage as well as the activation of alternative start sites for DNA replication when adjacent start sites are compromised by genotoxic drugs. It will be of interest in the future to see if this mechanism is universal to all tumour types that undergo EMT.
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