Glioblastoma Neurovascular Progenitor Orchestrates Tumor Cell Type Diversity.
Elisa Fazzari, Daria J Azizad, Kwanha Yu, Weihong Ge, Matthew X Li, Patricia R Nano, Ryan L Kan, Hong A Tum, Christopher Tse, Nicholas A Bayley, Vjola Haka, Dimitri Cadet, Travis Perryman, Jose A Soto, Brittney Wick, David R Raleigh, Elizabeth E Crouch, Kunal S Patel, Linda M Liau, Benjamin Deneen, David A Nathanson, Aparna Bhaduri
Author Information
Elisa Fazzari: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, Los Angeles, CA, USA. ORCID
Daria J Azizad: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, Los Angeles, CA, USA. ORCID
Kwanha Yu: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
Weihong Ge: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, Los Angeles, CA, USA. ORCID
Matthew X Li: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, Los Angeles, CA, USA. ORCID
Patricia R Nano: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, Los Angeles, CA, USA. ORCID
Ryan L Kan: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, Los Angeles, CA, USA. ORCID
Hong A Tum: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Christopher Tse: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Nicholas A Bayley: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. ORCID
Vjola Haka: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Dimitri Cadet: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. ORCID
Travis Perryman: Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, California, Los Angeles, CA, USA. ORCID
Jose A Soto: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, Los Angeles, CA, USA. ORCID
Brittney Wick: Genomics Institute, University of California Santa Cruz, Santa Cruz, CA, USA.
David R Raleigh: Department of Radiation Oncology, University of California San Francisco, San Francisco, California, USA.
Elizabeth E Crouch: Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA. ORCID
Kunal S Patel: Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, California, Los Angeles, CA, USA.
Linda M Liau: Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, California, Los Angeles, CA, USA. ORCID
Benjamin Deneen: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
David A Nathanson: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Aparna Bhaduri: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, Los Angeles, CA, USA. ORCID
Glioblastoma (GBM) is the deadliest form of primary brain tumor with limited treatment options. Recent studies have profiled GBM tumor heterogeneity, revealing numerous axes of variation that explain the molecular and spatial features of the tumor. Here, we seek to bridge descriptive characterization of GBM cell type heterogeneity with the functional role of individual populations within the tumor. Our lens leverages a gene program-centric meta-atlas of published transcriptomic studies to identify commonalities between diverse tumors and cell types in order to decipher the mechanisms that drive them. This approach led to the discovery of a tumor-derived stem cell population with mixed vascular and neural stem cell features, termed a neurovascular progenitor (NVP). Following validation and molecular characterization of NVP cells in GBM patient samples, we characterized their function Genetic depletion of NVP cells resulted in altered tumor cell composition, fewer cycling cells, and extended survival, underscoring their critical functional role. Clonal analysis of primary patient tumors in a human organoid tumor transplantation system demonstrated that the NVP has dual potency, generating both neuronal and vascular tumor cells. Although NVP cells comprise a small fraction of the tumor, these clonal analyses demonstrated that they strongly contribute to the total number of cycling cells in the tumor and generate a defined subset of the whole tumor. This study represents a paradigm by which cell type-specific interrogation of tumor populations can be used to study functional heterogeneity and therapeutically targetable vulnerabilities of GBM.
