Vessel co-option and radioresistance in glioblastoma

ended

Glioblastoma (GBM) is one of the deadliest types of human cancer. Despite a very aggressive treatment regime – including resection of the tumor, radiation and chemotherapy – its estimated recurrence rate is more than 90%. Recurrence is mostly caused by the regrowth of highly invasive cells spreading from the tumor bulk, which are not removed by resection. To develop an effective therapeutic approach, we need to better understand the underlying molecular mechanism of radiation resistance and tumor spreading in GBM. Radioresistance in GBM is attributed to glioma stem cells (GSCs), a fraction of perivascular, self-renewing, multipotent and tumor-initiating cells. Growing evidence highlights the perivascular space as a niche for GSC survival, resistance to therapy, progression and dissemination. The unknown factor is the dynamics of GSCs, how they end up in the vascular niche and how this impacts on radioresistance. My overall hypothesis is that GSCs reach the perivascular niche through vessel co-option - the directional migration of tumor cells towards vessels - and that targeting vessel co-option has the potential to radiosensitize GBM. With this project, we aim to uncover the exact molecular and cellular connections among vessel co-option, GSCs, the vascular niche and radioresistance. Using multiple strategies, such as multiphoton intravital microscopy, orthotopic models of GBM, organotypic cultures, screenings and survival studies, we will investigate and mechanistically change the dynamics of GSC and differentiated GBM cells in order to understand the role of their interaction with brain vessels and whether this confers resistance to radiotherapy. These studies will provide clinically relevant insights into the involvement of GSCs, the vascular niche and vessel co-option in the resistance of GBM to therapy. Since all GBM patients receive radiotherapy, many would benefit from therapeutic strategies aimed at increasing its efficacy.