The Phenotypes of Proliferating Glioblastoma Cells Reside on a Single Axis of Variation.
Lin Wang, Husam Babikir, Sören Müller, Garima Yagnik, Karin Shamardani, Francisca Catalan, Gary Kohanbash, Beatriz Alvarado, Elizabeth Di Lullo, Arnold Kriegstein, Sumedh Shah, Harsh Wadhwa, Susan M Chang, Joanna J Phillips, Manish K Aghi, Aaron A Diaz
Author Information
Lin Wang: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
Husam Babikir: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
Sören Müller: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
Garima Yagnik: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
Karin Shamardani: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
Francisca Catalan: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
Gary Kohanbash: Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
Beatriz Alvarado: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
Elizabeth Di Lullo: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California.
Arnold Kriegstein: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California.
Sumedh Shah: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
Harsh Wadhwa: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
Susan M Chang: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
Joanna J Phillips: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
Manish K Aghi: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
Aaron A Diaz: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California. aaron.diaz@ucsf.edu.
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...
