Sensitization of chondrosarcoma cells with PARP inhibitor and impact on cancer stem cells

International audienceChondrosarcoma is a primary tumour of bone and cartilage. One of the gold standard treatments is conventional X-ray therapy but chondrosarcomas of high malignancy are resistant. One of the mechanisms of radioresistance concerns the compartment of cancer stem cells (CSC) via their self-renewal and tumorogenesis capabilities. Radiosensitizing molecules, such as PARP inhibitors (PARPi) and carbon ions irradiation (C-ions), could overcome radioresistance and act on the CSC [1–3]. We investigated the cell survival and the impact on CSC of a chondrosarcoma line L835 in 2D and 3D culture models after X-ray compared to C-ray, in combination or not with PARPi.For the study of cell survival, we carried out clonogenic tests. For the study of the CSC, we wanted to determine the ability of cells to form tumospheres in wells containing a depleted culture medium. We also performed a kinetic analysis on 3D models of spheroids, using DNA damage tests (g-H2AX foci) and immunohistochemistry of ALDH, an enzyme more expressed in CSC.PARPi increased irradiation sensitivity with X-ray and in a lesser extent with C-ions, in 2D cultures. While X-ray alone did not appear to affect the number of tumospheres, we observed a decrease with exposure to PARPi alone and an increase in both X-ray and C-ions associated with PARPi. In 3D spheroids, the DNA damages increased immediately after irradiation, decreased 24 hours after irradiation in case of X-rays, and stayed constant in case of C-ions. Association of PARPi with irradiations did not modify this response. ALDH labeling of spheroids was very diffuse and did not reveal any modification in CSC proportions. This study highlights the complexity of the antitumor response to irradiations and the combination of treatment with PARPi, which can induce radiosensitization. Encouraging results are obtained with spheroids models, which appear relevant for studying the response of chondrosarcoma cells to irradiation with PARP inhibitor and the corresponding impact on cancer stem cells