The Phenotypes of Proliferating Glioblastoma Cells Reside on a Single Axis of Variation

• Published in: Cancer discovery Vol. 9; no. 12; pp. 1708 - 1719
• Main Authors: Wang, Lin, Babikir, Husam, Müller, Sören, Yagnik, Garima, Shamardani, Karin, Catalan, Francisca, Kohanbash, Gary, Alvarado, Beatriz, Di Lullo, Elizabeth, Kriegstein, Arnold, Shah, Sumedh, Wadhwa, Harsh, Chang, Susan M, Phillips, Joanna J, Aghi, Manish K, Diaz, Aaron A
• Format: Journal Article
• Language: English
• Published: United States 01.12.2019
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.cd-19-0329

Although tumor-propagating cells can be derived from glioblastomas (GBM) of the proneural and mesenchymal subtypes, a glioma stem-like cell (GSC) of the classic subtype has not been identified. It is unclear whether mesenchymal GSCs (mGSC) and/or proneural GSCs (pGSC) alone are sufficient to generate the heterogeneity observed in GBM. We performed single-cell/single-nucleus RNA sequencing of 28 gliomas, and single-cell ATAC sequencing for 8 cases. We found that GBM GSCs reside on a single axis of variation, ranging from proneural to mesenchymal. lineage tracing using both transcriptomics and genetics supports mGSCs as the progenitors of pGSCs. Dual inhibition of pGSC-enriched and mGSC-enriched growth and survival pathways provides a more complete treatment than combinations targeting one GSC phenotype alone. This study sheds light on a long-standing debate regarding lineage relationships among GSCs and presents a paradigm by which personalized combination therapies can be derived from single-cell RNA signatures, to overcome intratumor heterogeneity. SIGNIFICANCE: Tumor-propagating cells can be derived from mesenchymal and proneural glioblastomas. However, a stem cell of the classic subtype has yet to be demonstrated. We show that classic-subtype gliomas are comprised of proneural and mesenchymal cells. This study sheds light on a long-standing debate regarding lineage relationships between glioma cell types. . .