The meningioma enhancer landscape delineates novel subgroups and drives druggable dependencies

Briana C. Prager, Harish N. Vasudevan, Deobrat Dixit, Jean A. Bernatchez, Qiulian Wu, Lisa C. Wallace, Shruti Bhargava, Derrick Lee, Bradley H. King, Andrew R. Morton, Ryan C. Gimple, Melike Pekmezci, Zhe Zhu, Jair L. Siqueira-Neto, Xiuxing Wang, Qi Xie, Clark Chen, Gene H. Barnett, Michael A. Vogelbaum, Stephen C. MackLukas Chavez, Arie Perry, David R. Raleigh, Jeremy N. Rich

Research output: Contribution to journalArticlepeer-review

Abstract

Meningiomas are the most common primary intracranial tumor with current classification offering limited therapeutic guidance. Here, we interrogated meningioma enhancer landscapes from 33 tumors to stratify patients based upon prognosis and identify novel meningioma-specific dependencies. Enhancers robustly stratified meningiomas into three biologically distinct groups (adipogenesis/cholesterol, mesodermal, and neural crest) distinguished by distinct hormonal lineage transcriptional regulators. Meningioma landscapes clustered with intrinsic brain tumors and hormonally responsive systemic cancers with meningioma subgroups, reflecting progesterone or androgen hormonal signaling. Enhancer classification identified a subset of tumors with poor progno-sis, irrespective of histologic grading. Superenhancer signatures predicted drug dependencies with superior in vitro efficacy to treatment based upon the NF2 genomic profile. Inhibition of DUSP1, a novel and druggable meningioma target, impaired tumor growth in vivo. Collectively, epigenetic landscapes empower meningioma classification and identification of novel therapies. SIGNIFICANCE: Enhancer landscapes inform prognostic classification of aggressive meningiomas, identifying tumors at high risk of recurrence, and reveal previously unknown therapeutic targets. Drug-gable dependencies discovered through epigenetic profiling potentially guide treatment of intractable meningiomas.

Original languageEnglish (US)
Pages (from-to)1722-1741
Number of pages20
JournalCancer discovery
Volume10
Issue number11
DOIs
StatePublished - Nov 2020

Bibliographical note

Funding Information:
This work was supported by grants provided by NIH (CA217066, to B.C. Prager; CA217065, to R.C. Gimple; CA197718, CA238662, NS103434, to J.N. Rich), CPRIT award, ALSF Young Investigator Award, Rally Research Grant, BEAR Necessities Pediatric Cancer Foundation Grant, Children’s Cancer Research Fund award, and Baylor College of Medicine Junior Faculty Award (to S.C. Mack). We appreciate critical input and feedback from the members of the Rich laboratory. We also thank the Gillespie lab at the University of Alabama-Birmingham and the Jensen lab at the University of Utah for providing CH157-MN and IOMM-Lee cells, respectively. We appreciate the assistance of Mary McGraw and Dr. Christopher Hubert in obtaining samples. We also thank the patients and donors who

Funding Information:
This work was supported by grants provided by NIH (CA217066, to B.C. Prager; CA217065, to R.C. Gimple; CA197718, CA238662, NS103434, to J.N. Rich), CPRIT award, ALSF Young Investigator Award, Rally Research Grant, BEAR Necessities Pediatric Cancer Foundation Grant, Children?s Cancer Research Fund award, and Baylor College of Medicine Junior Faculty Award (to S.C. Mack). We appreciate critical input and feedback from the members of the Rich laboratory. We also thank the Gillespie lab at the University of Alabama-Birmingham and the Jensen lab at the University of Utah for providing CH157-MN and IOMM-Lee cells, respectively. We appreciate the assistance of Mary McGraw and Dr. Christopher Hubert in obtaining samples. We also thank the patients and donors whoprovided the tissue used in this study and acknowledge Dr. Richard Drake and Dr. Jennifer McBride from the Cleveland Clinic for their assistance in deriving arachnoid granulation models.

Publisher Copyright:
© 2020 American Association for Cancer Research.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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