Radioresistance of tumor cells constitutes the primary cause of tumor recurrence and relapse. Cancer stem cells (CSC) could be in large part responsible for the inherent radioresistance of a different number of tumors. Particularly relevant is the finding that patient-derived as well as cultured CSCs exhibit a robust DNA Damage Response (DDR) as compared to relatively more differentiated malignant cells. It is believed that enhanced DDR could result from a general adaptation to high levels of DNA replication stress already active in untreated cells and that will cause and increase activation of DDR after irradiation thereby contributing to tumor radioresistance. Promotion of CSCs properties can result also from dysregulation of miRNAs. The mechanisms underlying CSC's refractoriness to radiation remain still poorly understood.
We found that a chronic treatment with a low dose radiation (LDR) determines a radioadaptive response to IR-induced chromosome breaks that renders Drosophila mitotic cells more resistant than untreated cells to DNA damage. Our analyses reveal that the radioadaptive response shares common features with that observed in tumor cells and in CSCs that are resistant to IR. Remarkably some of the genes that are modulated in radioadapted Drosophila cells are also involved in regulation of stemness and encode Drosophila orthologs of human proteins (i.e. the RNA binding protein TARBP2, a member of the RISC complex) with roles in CSC and tumor progression. We will use fruitflies as an animal model for providing new information on the mechanisms of radioresistance and for unveiling conserved factors involved in CSC radioresistance. We believe that these results will be clinically relevant for tumor biology.
Understanding the molecular bases of radioresistance is clinically relevant for tumor biology as it represents a major determinant of the radiotherapy outcome and prognosis in tumor patients. By the identification and characterization in flies of new factors involved in radioresistance we will generate important information to decipher the molecular mechanisms underlying radioresistance and unravel an unanticipated role for Loqs/TARBP2 in regulating tumor cells and CSCs survival upon irradiation.
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