The use of organoids in the study of radiation response and therapeutic window

The efficacy of radiotherapy cancer treatment is hindered by tumor radioresistance and normal tissue side effects. In this thesis, in vitro stem cell-derived organoid models were developed and used to assess the contribution of both cancer and normal tissue stem cells in the radiation response, to study potential ways to optimize radiotherapy. The 3D nature of organoids may offer a radiation response model that better reflects the patient-specific in vivo response than traditional in vitro 2D cell line models. Many factors contribute to tumor radioresistance, however cancer stem cells related treatment resistance may play an important role. Using esophageal cancer organoids, the potential of altering the cancer stem cell population on reducing tumor radioresistance was assessed. Normal tissue side effects arise from unavoidable co-irradiation of normal tissue. Importantly the homeostasis of the normal tissue may be restored by surviving tissue stem cells. Reducing the dose to normal tissue is currently used in an attempt to reduce normal tissue side effects. However, the effects of a reduced dose to the normal tissue stem cells is not known. In this thesis, organoids are used to study the effects of different types of irradiation on normal tissue stem cells, while the effect of relatively low doses of irradiation on normal tissue was also investigated. It was shown that relatively low doses of irradiation have a disproportionately large impact on tissue function. Together, the work in this thesis contributes to the understanding of mechanisms which contribute to radioresistance and to radiation-induced side effects