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

Overview

Journal Cancer Discov

Specialty Oncology

Date 2019 Sep 27

PMID 31554641

Citations 169

Authors

Lin Wang

Husam Babikir

Soren Muller

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

Affiliations

Soon will be listed here.

Abstract

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...

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