WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma

Area of Science:

• Oncology
• Epigenetics
• Cancer Stem Cell Biology

Background:

• Glioblastomas (GBMs) are aggressive brain tumors characterized by heterogeneity and resistance to therapy.
• Cancer stem cells (CSCs) drive GBM recurrence and treatment failure, yet their maintenance mechanisms are not fully understood.
• Targeting CSCs is crucial for developing effective GBM therapies.

Purpose of the Study:

• To identify epigenetic regulators essential for maintaining therapy-resistant glioblastoma cancer stem cells (CSCs).
• To investigate the role of WDR5 in glioblastoma CSC maintenance and therapeutic resistance.
• To evaluate WDR5 inhibition as a potential therapeutic strategy for glioblastomas.

Main Methods:

• Spatially resolved loss-of-function screen in patient-derived glioblastoma organoids.
• Assessment of WDR5's role in the WRAD complex and histone H3 Lysine 4 trimethylation (H3K4me3).
• Analysis of gene expression, transcription factor motifs (POU, OCT4, SOX2), CSC reporter activity, and in vitro/in vivo tumor growth.

Main Results:

• WDR5 was identified as indispensable for maintaining the SOX2-enriched, therapy-resistant CSC niche in glioblastomas.
• WDR5 inhibition disrupted WRAD complex assembly, reduced H3K4me3 levels, and decreased expression of CSC-associated oncogenic genes.
• WDR5 inhibition diminished CSCs with high OCT4::SOX2 reporter activity, impaired CSC self-renewal, and reduced tumor growth in vitro and in vivo.

Conclusions:

• WDR5 and the WRAD complex are critical for maintaining the glioblastoma CSC state and promoting tumor growth.
• Targeting WDR5 represents a promising therapeutic avenue for glioblastomas and potentially other advanced cancers.
• WDR5 inhibition offers a novel strategy to overcome treatment resistance in glioblastoma by targeting cancer stem cells.