Open Access
Transcription elongation factors represent in vivo cancer dependencies in glioblastoma
Tyler E. Miller,Tyler E. Miller,Brian B. Liau,Brian B. Liau,Lisa C. Wallace,Andrew R. Morton,Andrew R. Morton,Qi Xie,Deobrat Dixit,Daniel C. Factor,Leo J.Y. Kim,Leo J.Y. Kim,James J. Morrow,Qiulian Wu,Stephen C. Mack,Stephen C. Mack,Christopher G. Hubert,Christopher G. Hubert,Shawn M. Gillespie,Shawn M. Gillespie,William A. Flavahan,William A. Flavahan,Thomas Hoffmann,Rohit Thummalapalli,Rohit Thummalapalli,Michael T. Hemann,Patrick J. Paddison,Craig Horbinski,Johannes Zuber,Peter C. Scacheri,Bradley E. Bernstein,Bradley E. Bernstein,Paul J. Tesar,Jeremy N. Rich,Jeremy N. Rich,Jeremy N. Rich +35 more
TLDR
The power of in vivo phenotypic screening to identify new classes of ‘cancer dependencies’ not identified by previous in vitro approaches is demonstrated, and could supply new opportunities for therapeutic intervention.Abstract:
Glioblastoma is a universally lethal cancer with a median survival time of approximately 15 months. Despite substantial efforts to define druggable targets, there are no therapeutic options that notably extend the lifespan of patients with glioblastoma. While previous work has largely focused on in vitro cellular models, here we demonstrate a more physiologically relevant approach to target discovery in glioblastoma. We adapted pooled RNA interference (RNAi) screening technology for use in orthotopic patient-derived xenograft models, creating a high-throughput negative-selection screening platform in a functional in vivo tumour microenvironment. Using this approach, we performed parallel in vivo and in vitro screens and discovered that the chromatin and transcriptional regulators needed for cell survival in vivo are non-overlapping with those required in vitro. We identified transcription pause-release and elongation factors as one set of in vivo-specific cancer dependencies, and determined that these factors are necessary for enhancer-mediated transcriptional adaptations that enable cells to survive the tumour microenvironment. Our lead hit, JMJD6, mediates the upregulation of in vivo stress and stimulus response pathways through enhancer-mediated transcriptional pause-release, promoting cell survival specifically in vivo. Targeting JMJD6 or other identified elongation factors extends survival in orthotopic xenograft mouse models, suggesting that targeting transcription elongation machinery may be an effective therapeutic strategy for glioblastoma. More broadly, this study demonstrates the power of in vivo phenotypic screening to identify new classes of 'cancer dependencies' not identified by previous in vitro approaches, and could supply new opportunities for therapeutic intervention.read more
Citations
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Reconstructing and Reprogramming the Tumor-Propagating Potential of Glioblastoma Stem-like Cells
Mario L. Suvà,Esther Rheinbay,Shawn M. Gillespie,Anoop P. Patel,Hiroaki Wakimoto,Samuel D. Rabkin,Nicolo Riggi,Andrew S. Chi,Daniel P. Cahill,Brian V. Nahed,William T. Curry,Robert L. Martuza,Miguel Rivera,Nikki E. Rossetti,Simon Kasif,Samantha Beik,Sabah Kadri,Itay Tirosh,Ivo Wortman,Alex K. Shalek,Orit Rozenblatt-Rosen,David N. Louis,Bradley E. Bernstein,Aviv Regev +23 more
TL;DR: This study identifies a core set of neurodevelopmental TFs (POU3F2, SOX2, SALL2, and OLIG2) essential for GBM propagation and reconstructs a network model that highlights critical interactions and identifies candidate therapeutic targets for eliminating TPCs.
Journal ArticleDOI
Current Challenges and Opportunities in Treating Glioblastoma
TL;DR: Novel drug delivery methods, including nanoparticles and prodrugs and computational multi-parameter optimization to assess the blood-brain barrier (BBB) permeability of small molecules in clinical trials for GBM treatment are discussed.
Journal ArticleDOI
An anatomic transcriptional atlas of human glioblastoma
Ralph B. Puchalski,Nameeta Shah,Jeremy A. Miller,Rachel A. Dalley,Steve R. Nomura,Jae Guen Yoon,Kimberly A. Smith,Michael Lankerovich,Darren Bertagnolli,Kris Bickley,Andrew F. Boe,Krissy Brouner,Stephanie Butler,Shiella Caldejon,Mike Chapin,Suvro Datta,Nick Dee,Tsega Desta,Tim A. Dolbeare,Nadezhda Dotson,Amanda Ebbert,David Feng,Xu Feng,Michael S. Fisher,Garrett Gee,Jeff Goldy,Lindsey Gourley,Benjamin W. Gregor,Guangyu Gu,Nika Hejazinia,John G. Hohmann,Parvinder Hothi,Robert Howard,Kevin M. Joines,Ali Kriedberg,Leonard Kuan,Chris Lau,Felix Lee,Hwahyung Lee,Tracy Lemon,Fuhui Long,Naveed Mastan,Erika Mott,Chantal Murthy,Kiet Ngo,Eric Olson,Melissa Reding,Zack Riley,David Rosen,David Sandman,Nadiya V. Shapovalova,Clifford R. Slaughterbeck,Andrew Sodt,Graham Stockdale,Aaron Szafer,Wayne Wakeman,Paul Wohnoutka,Steven J. White,Don Marsh,Robert C. Rostomily,Robert C. Rostomily,Lydia Ng,Chinh Dang,Allan R. Jones,Bart Keogh,Haley Gittleman,Jill S. Barnholtz-Sloan,Patrick J. Cimino,Megha S Uppin,C. Dirk Keene,Farrokh Farrokhi,Justin D. Lathia,Michael E. Berens,Antonio Iavarone,Amy Bernard,Ed S. Lein,John W. Phillips,Steven Rostad,Charles Cobbs,Michael Hawrylycz,Greg Foltz +80 more
TL;DR: The Ivy Glioblastoma Atlas is presented, an anatomically based transcriptional atlas of human gliOBlastoma that aligns individual histologic features with genomic alterations and gene expression patterns, thus assigning molecular information to the most important morphologic hallmarks of the tumor.
Journal ArticleDOI
Cancer Stem Cells: The Architects of the Tumor Ecosystem.
TL;DR: This Perspective discusses how CSCs are active architects of their microenvironment and drive interactions with other tumor components, such as immune cells, cancer-associated fibroblasts and differentiated cells, blood vessels, and other extracellular cues to engineer a sustainable niche.
Journal ArticleDOI
Epidermal growth factor receptor and EGFRvIII in glioblastoma: signaling pathways and targeted therapies.
TL;DR: Signaling pathways mediated by EGFR/EGFRvIII, current therapeutics, and novel strategies to target EGFR-tyrosine kinase inhibitors (TKIs) or antibodies are discussed.
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