Chemotherapy is still the most widely used treatment for advanced cancer. But tumors often become resistant, which worsens the prognosis. Researchers from the Université Libre de Bruxelles and the DNA Replication Group of the CNIO (Spanish National Cancer Research Center) have discovered one of the causes of skin cancer becoming resistant to chemotherapy, and present their results in Nature.
Cancers of the epithelia, which are the tissues covering all body surfaces -the skin, but also the linings of the organs- are related to a type of change that epithelial cells undergo, called epithelial-mesenchymal transition. In this process, cells detach from their neighbors and acquire invasive properties, which help them colonize surrounding tissues and spread throughout the organism.
It was known that the epithelial-mesenchymal transition also plays a role in tumors becoming resistant to chemotherapy, but it was not known exactly why. The new result points to a protein called RHOJ. The work, led by researcher Cédric Blanpain, from the Université Libre de Bruxelles, is co-authored by CNIO researchers Sara Rodríguez-Acebes and Juan Méndez.
The researchers observed, in mouse models of skin cancer, that the expression of the RHOJ protein is especially high in chemotherapy-resistant cells. Indeed, they found that cancer cells become vulnerable to chemotherapy again when RHOJ is no longer expressed. In other words, inhibiting the RHOJ protein makes the cancer cells respond to treatment again.
The authors show that RHOJ triggers the formation of long actin protein filaments and promotes the repair of chemotherapy-induced DNA damage. It thus helps the cancer cell survive treatment.
“It has been very interesting to discover that chemotherapy resistance in cancers with EMT is controlled in part by DNA replication and repair mechanisms,” says Méndez.
“It’s another example of how basic research into these cellular processes allows us to address a problem with major clinical implications.”
Image: Mouse epithelial cells. Below, DNA fibers undergoing replication before and after chemotherapy treatment. Credit: CNIO
Reference: Debaugnies, M., Rodríguez-Acebes, S., Blondeau, J. et al. RHOJ controls EMT-associated resistance to chemotherapy. Nature 616, 168–175 (2023). https://doi.org/10.1038/s41586-023-05838-7
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