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361 WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma
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- Christopher Hubert, Kelly Mitchell, Samuel Sprowls, Sajina Shakya, Sonali Arora, Daniel J. Silver, Christopher M. Goins, Lisa Wallace, Gustavo Roversi, Rachel Schafer, Kristen Kay, Tyler E. Miller, Adam Lauko, John Bassett, Anjali Kashyap, J. D’Amato Kass, Erin E. Mulkearns-Hubert, Sadie Johnson, Joseph Alvarado, Jeremy N. Rich, Patrick J. Paddison, Anoop P. Patel, Shaun R. Stauffer, Christopher G. Hubert, Justin D. Lathia
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- Journal:
- Journal of Clinical and Translational Science / Volume 7 / Issue s1 / April 2023
- Published online by Cambridge University Press:
- 24 April 2023, p. 107
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- Article
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OBJECTIVES/GOALS: Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). In this study, we perform an epigenetic-focused functional genomics screen in GBM organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche. METHODS/STUDY POPULATION: Despite their importance for tumor growth, 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. Our niche-specific screens identified WDR5, an H3K4 histone methyltransferase responsible for activating specific gene expression, as indispensable for GBM CSC growth and survival. RESULTS/ANTICIPATED RESULTS: In GBM CSC models, 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, required for stem cell maintenance and including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment resulted in dose-dependent silencing of stem cell reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSC in vitro growth and self-renewal as well as in vivo tumor growth. DISCUSSION/SIGNIFICANCE: Our results unveiled the role of WDR5 in maintaining the CSC state in GBM and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers. This conceptual and experimental framework can be applied to many cancers, and can unmask unique microenvironmental biology and rationally designed combination therapies.
Rogues' Gallery of Contributing Authors
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- By Ramon Abola, Rishimani Adsumelli, Syed Azim, Tazeen Beg, Helene Benveniste, Louis Chun, Ramtin Cohanim, Dominick Coleman, Joseph Conrad, Tommy Corrado, Jason Daras, Michelle DiGuglielmo, Vedan Djesevic, Andrew Drollinger, Kathleen Dubrow, Brian Durkin, Ralph Epstein, Christopher J. Gallagher, Xiaojun Guo, Sofie Hussain, Ron Jasiewicz, Anna Kogan, Ursula Landman, Rany Makaryus, Daryn Moller, Tate Montgomery, Matthew Neal, Khoa Nguyen, Marco Palmieri, Shaji Poovathor, Eric Posner, Deborah Richman, Andrew Rozbruch, Misako Sakamaki, Joy Schabel, Bharathi Scott, Peggy Seidman, Shiena Sharma, Vishal Sharma, Ellen Steinberg, Neera Tewari, Jane Yi, Jonida Zeqo, Peter Chung, John Denny, Steven H. Ginsberg, Jeremy Grayson, Jonathan Kraidin, Stephen Lemke, Tejal Patel, Salvatore Zisa, Charles Cowles, Marc Rozner, Shawn Banks, Deborah Brauer, Lebron Cooper, V. Samepathi David, Steve Gayer, Steven Gil, Eric A. Harris, Murlikrishna Kannan, Michael C. Lewis, David A. Lindley, Carlos M. Mijares, Sana Nini, Shafeena Nurani, Sujatha Pentakota, Edgar Pierre, Amy Klash Pulido, Michael Rossi, Miguel Santos, Nancy Setzer-Saade, Adam Sewell, Omair H. Toor, Ashish Udeshi, Patricia Wawroski, Lauren C. Berkow, Dan Berkowitz, Ramola Bhambhani, Kerry K. Blaha, Veronica Busso, Adam J. Carinci, Paul J. Christo, R. Blaine Easley, Ralph J. Fuchs, Samuel M. Galvagno, Nishant Gandhi, Andrew Goins, Robert S. Greenberg, Sayeh Hamzehzadeh, Theresa L. Hartsell, Eugenie Heitmiller, Jeremy M. Huff, Brijen L. Joshi, Sapna Kudchadkar, Jennifer K. Lee, Ira Lehrer, Peter Lin, Justin Lockman, Christine L. Mai, Christina Miller, Nanhi Mitter, Gillian Newman, Daniel Nyhan, Lale Odekon, Rabi Panigrahi, Melissa Pant, Alexander Papangelou, Mark Rossberg, Adam Schiavi, Steven J. Schwartz, Deborah A. Schwengel, Brandon M. Togioka, Tina Tran, Emmett Whitaker, Bradford D. Winters, Christopher Wu, Elena J. Holak, Paul S. Pagel
- Edited by Christopher J. Gallagher, State University of New York, Stony Brook, Michael C. Lewis, University of Miami School of Medicine, Deborah A. Schwengel
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- Book:
- Core Clinical Competencies in Anesthesiology
- Published online:
- 06 July 2010
- Print publication:
- 12 April 2010, pp xi-xii
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