SLUG and Truncated TAL1 Reduce Glioblastoma Stem Cell Growth Downstream of Notch1 and Define Distinct Vascular Subpopulations in Glioblastoma Multiforme

SIMPLE SUMMARY: Glioblastoma multiforme is the most aggressive form of brain tumor and is still incurable. These neoplasms are particularly difficult to treat efficiently because of their highly heterogeneous and resistant characteristics. Advances in genomics have highlighted the complex molecular landscape of these tumors and the need to further develop effective and targeted therapies for each patient. A specific population of cells with enriched stem cell properties within tumors, i.e., glioblastoma stem cells (GSC), drives this cellular heterogeneity and therapeutical resistance, and thus constitutes an attractive target for the design of innovative treatments. However, the signals driving the maintenance and resistance of these cells are still unclear. We provide new findings regarding the expression of two transcription factors in these cells and directly in glioblastoma patient samples. We show that these proteins downregulate GSC growth and ultimately participate in the progression of gliomas. The forthcoming results will contribute to a better understanding of gliomagenesis. ABSTRACT: Glioblastomas (GBM) are high-grade brain tumors, containing cells with distinct phenotypes and tumorigenic potentials, notably aggressive and treatment-resistant multipotent glioblastoma stem cells (GSC). The molecular mechanisms controlling GSC plasticity and growth have only partly been elucidated. Contact with endothelial cells and the Notch1 pathway control GSC proliferation and fate. We used three GSC cultures and glioma resections to examine the expression, regulation, and role of two transcription factors, SLUG (SNAI2) and TAL1 (SCL), involved in epithelial to mesenchymal transition (EMT), hematopoiesis, vascular identity, and treatment resistance in various cancers. In vitro, SLUG and a truncated isoform of TAL1 (TAL1-PP22) were strongly upregulated upon Notch1 activation in GSC, together with LMO2, a known cofactor of TAL1, which formed a complex with truncated TAL1. SLUG was also upregulated by TGF-β1 treatment and by co-culture with endothelial cells. In patient samples, the full-length isoform TAL1-PP42 was expressed in all glioma grades. In contrast, SLUG and truncated TAL1 were preferentially overexpressed in GBMs. SLUG and TAL1 are expressed in the tumor microenvironment by perivascular and endothelial cells, respectively, and to a minor extent, by a fraction of epidermal growth factor receptor (EGFR) -amplified GBM cells. Mechanistically, both SLUG and truncated TAL1 reduced GSC growth after their respective overexpression. Collectively, this study provides new evidence for the role of SLUG and TAL1 in regulating GSC plasticity and growth.