P10.02.B The fragile balance between proliferation and neoplasia in neural stem cells: role of DIAPH3 in glioblastoma

Abstract

Abstract Background DIAPH3 belongs to the formin family of proteins that are master regulators of the cell cytoskeleton. DIAPH3 plays a key role in cytokinesis as well karyokinesis. Hence, in the mouse brain, DIAPH3-deficient neural stem cells exhibit abnormal cell division leading to aneuploidy and apoptosis of cells progeny. Given the importance of aneuploidy in cancer development and progression, we asked whether DIAPH3 loss could be involved in the genesis and the aggressiveness of brain tumors. Material and Methods We co-inactivated Diaph3 and Trp53 genes in the mouse cerebral cortex using the Emx1-Cre mouse line (Diaph3/Trp53 dcKO). As a control, we inactivated only Trp53 gene using the same Cre mouse line (Trp53 cKO). Mouse survival was analyzed, and tumors were collected for histological analysis as well as molecular characterization. Additionally, we measured DIAPH3 expression in human glioblastoma samples and studied its impact on patient overall survival. Results Diaph3/Trp53 dcKO develop brain tumors earlier compared to Trp53 cKO resulting in a decrease of mouse survival. Hematoxylin-eosin staining, as well as GFAP, OLIG2 and KI67 immunostainings strongly suggest that the tumors are glioblastomas. Quantitative reverse transcription PCR performed on biopsies from 73 patients uncover variable DIAPH3 expression levels in glioblastoma samples. Interestingly, multivariate Cox proportional-hazards analysis shows that low DIAPH3 expression predicts a worse overall survival, independently from other known prognosis factors. Conclusion On one hand, our study shows that DIAPH3 loss favors glioblastoma development in mouse, strongly suggesting a tumor-suppressor role for DIAPH3. On the other hand, the clinical study shows that DIAPH3 low expression has a negative impact on patient overall survival indicating that DIAPH3 loss may favor resistance to chemotherapy and/or radiotherapy.