Radiation-induced proneural-to-mesenchymal transition in glioblastoma: how does it work and how can it be prevented?

Glioblastomas (GBM) are malignant brain tumors that derive from progenitor cells or neuroglial stem cells. GBM are the most common primary brain tumors in adults and are treated with maximal surgical resection, radiotherapy and chemotherapy. However, the presence of chemo- and radioresistant cancer stem cells renders the treatment merely life-prolonging with a median 5-year survival of no more than 15 months. Investigating the molecular characteristics of individual GBM could therefore provide important insights and subsequently improved treatment strategies to enhance the survival of these cancer patients. GBM tumor cells have been observed to exist in different molecular subtypes, each with a certain level of radiosensitivity. These include the radiosensitive proneural cells and the radioresistant mesenchymal cells. Treatment efficacy is hampered by this intra-tumor heterogeneity as mesenchymal cells are more resistant to radiotherapy than proneural cells. Moreover, the plasticity of these cells allows a phenotypic shift from the proneural subtype to the mesenchymal subtype, a process that can be triggered by radio- and chemotherapy. This radiation-induced proneural-to-mesenchymal transition (PMT) can therefore turn radiosensitive cells and tumors into radioresistant ones which relates to therapy resistance and the recurrence of GBM. This project focusses on the investigation of the molecular mechanisms underlying radiation-induced PMT and whether this mesenchymal differentiation can be blocked in vitro and in vivo. The ultimate goal is to render the tumor more sensitive to different treatments and to open up interesting new avenues for the development of improved treatment strategies for GBM.