P19.01.a investigating the morphological heterogeneity of glioblastoma stem cells and its role in tumour proliferation and invasiveness

Abstract BACKGROUND Glioblastoma is the most common and aggressive primary brain tumour. Cancer hijacks developmental pathways and several studies have identified a stem cell-like population in glioblastoma following neurodevelopmental trajectories. In the foetal neocortex, a type of neural stem cell called basal progenitor is thought to be responsible for neocortical expansion. Basal progenitors exist in different morphotypes, and greater morphological complexity underlies their increased proliferation. We thus propose that cell morphology also plays a role in the proliferation and invasiveness of glioblastoma stem cells. MATERIAL AND METHODS We characterise the morphological heterogeneity of glioblastoma stem cells by immunostaining of human primary bulk tumour and peritumoral tissue. To then understand the function of cell morphology in tumour progression, we genetically manipulate morpho-regulatory molecules in 2D glioblastoma stem cells that show a genetic dependency on the target molecules based on cancer dependency maps. RESULTS We show that glioblastoma stem cells have a vast morphological heterogeneity in human primary bulk tumour and peritumoral tissue. The morphotypes observed are conserved in 2D glioblastoma stem cells and they are reminiscent of neural progenitors in the developing neocortex. We then test whether the genetic manipulation of those morpho-regulatory molecules which control the proliferation of basal progenitors in the fetal neocortex also affects the proliferation and invasiveness of glioblastoma stem cells. CONCLUSION Glioblastoma stem cells display extensive morphological heterogeneity, like basal progenitors in the developing neocortex. Morpho-regulatory molecules do not only control cell shape but may contribute to the proliferation and invasiveness of glioblastoma stem cells. We envision that the identification of morpho-regulatory molecules controlling tumour progression will open new therapeutic windows through pharmacological targeting and drug repurposing.