WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma
- Kelly Mitchell1,2,
- Samuel A. Sprowls1,2,13,
- Sonali Arora3,13,
- Sajina Shakya1,
- Daniel J. Silver1,2,4,
- Christopher M. Goins5,
- Lisa Wallace1,
- Gustavo Roversi1,4,
- Rachel E. Schafer1,4,
- Kristen Kay1,
- Tyler E. Miller6,7,
- Adam Lauko1,4,8,9,
- John Bassett3,
- Anjali Kashyap1,
- Jonathan D'Amato Kass1,
- Erin E. Mulkearns-Hubert1,4,
- Sadie Johnson1,
- Joseph Alvarado5,
- Jeremy N. Rich10,
- Eric C. Holland3,
- Patrick J. Paddison3,
- Anoop P. Patel3,11,
- Shaun R. Stauffer5,14,
- Christopher G. Hubert1,2,4,14 and
- Justin D. Lathia1,2,4,12,14
- 1Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA;
- 2Case Comprehensive Cancer Center, Cleveland, Ohio 44106, USA;
- 3Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington 98109, USA;
- 4Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44106, USA;
- 5Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA;
- 6Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
- 7Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA;
- 8Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA;
- 9Medical Scientist Training Program, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA;
- 10University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA;
- 11Department of Neurological Surgery, University of Washington, Seattle, Washington 98195, USA;
- 12Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio 44106, USA
- Corresponding authors: lathiaj{at}ccf.org, christopher.hubert{at}case.edu
Abstract
Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors driven by populations of cancer stem cells (CSCs). However, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy-resistant niche and identified WDR5 as indispensable for this population. WDR5 is a component of the WRAD complex, which promotes SET1 family-mediated Lys4 methylation of histone H3 (H3K4me), associated with positive regulation of transcription. In GBM CSCs, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, including the POU5F1(OCT4)::SOX2 motif. Use of a SOX2/OCT4 reporter demonstrated that WDR5 inhibitor treatment diminished cells with high reporter activity. Furthermore, WDR5 inhibitor treatment and WDR5 knockdown altered the stem cell state, disrupting CSC in vitro growth and self-renewal, as well as in vivo tumor growth. These findings highlight the role of WDR5 and the WRAD complex in maintaining the CSC state and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.349803.122.
- Received June 6, 2022.
- Accepted January 3, 2023.
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