Glioblastoma CD105(+) cells define a SOX2(-) cancer stem cell-like subpopulation in the pre-invasive niche.

Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in adults. Glioma stem like cells (GSC) represent the highest cellular hierarchy in GBM and have a determining role in tumor growth, recurrence and patient prognosis. However, a better definition of GSC subpopulations, especially at the surgical resection margin, is warranted for improved oncological treatment options. The present study interrogated cells expressing CD105 (CD105(+)) specifically within the tumor front and the pre-invasive niche as a potential GSC subpopulation. GBM primary cell lines were generated from patients (n = 18) and CD105(+) cells were isolated and assessed for stem-like characteristics. In vitro, CD105(+) cells proliferated and enriched in serum-containing medium but not in serum-free conditions. CD105(+) cells were characterized by Nestin(+), Vimentin(+) and SOX2(-), clearly distinguishing them from SOX2(+) GCS. GBM CD105(+) cells differentiated into osteocytes and adipocytes but not chondrocytes. Exome sequencing revealed that GBM CD105(+) cells matched 83% of somatic mutations in the Cancer cell line encyclopedia, indicating a malignant phenotype and in vivo xenotransplantation assays verified their tumorigenic potential. Cytokine assays showed that immunosuppressive and protumorigenic cytokines such as IL6, IL8, CCL2, CXCL-1 were produced by CD105(+) cells. Finally, screening for 88 clinical drugs revealed that GBM CD105(+) cells are resistant to most chemotherapeutics except Doxorubicin, Idarubicin, Fludarabine and ABT-751. Our study provides a rationale for targeting tumoral CD105(+) cells in order to reshape the tumor microenvironment and block GBM progression.