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Enhancer reprogramming in PRC2-deficient malignant peripheral nerve sheath tumors induces a targetable de-differentiated state

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Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that frequently harbor genetic alterations in polycomb repressor complex 2 (PRC2) components—SUZ12 and EED. Here, we show that PRC2 loss confers a dedifferentiated early neural-crest phenotype which is exclusive to PRC2-mutant MPNSTs and not a feature of neurofibromas. Neural crest phenotype in PRC2 mutant MPNSTs was validated via cross-species comparative analysis using spontaneous and transgenic MPNST models. Systematic chromatin state profiling of the MPNST cells showed extensive epigenomic reprogramming or chromatin states associated with PRC2 loss and identified gains of active enhancer states/super-enhancers on early neural crest regulators in PRC2-mutant conditions around genomic loci that harbored repressed/poised states in PRC2-WT MPNST cells. Consistently, inverse correlation between H3K27me3 loss and H3K27Ac gain was noted in MPNSTs. Epigenetic editing experiments established functional roles for enhancer gains on DLX5—a key regulator of neural crest phenotype. Consistently, blockade of enhancer activity by bromodomain inhibitors specifically suppressed this neural crest phenotype and tumor burden in PRC2-mutant PDXs. Together, these findings reveal accumulation of dedifferentiated neural crest like state in PRC2-mutant MPNSTs that can be targeted by enhancer blockade.

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Acknowledgements

We thank Amy Ninetto for critical input and editing of the manuscript. We thank Erika Thompson, the Advanced Technology Genomics Core Facility (NCI Grant CA016672(ATGC), the Research Animal Support Facility, the Advanced Microscopy Core Facility (funded by NIH S10 RR029552), Functional Genomics Core (NCI Cancer Center Support Grant (P30 CA016672), Cytogenetics and Cell Authentication core, MD Anderson Cancer Center Clinical Core and MD Anderson Cancer Center Science Park Research Histology, Pathology and Imaging Core (supported by P30 CA16672 DHHS/NCI Cancer Center Support Grant). This work was partially supported by Department of Defense CDRMP Grant (NF160026 to K.E.T and NF190074 to K.R.), to K.E.T., The Texas Neurofibromatosis Foundation, The Sally Kingsbury Sarcoma Research Foundation to K.E.T. and DoD New Investigator Award to Kunal Rai (NF190074). V.K and S.M.L were funded by The Jay Vernon Jackson Sarcoma Research Fund and Friends MDA Sarcoma Research. Support for the clinical sample collection was provided by the Ferrin R Zeitlin Foundation, Artz Cure Sarcoma Foundation (K.E.T.) and A Shelter for Cancer Families (formerly Amschwand Sarcoma Cancer Foundation) (K.E.T). Support for the proteomics analysis was from MoJo’s Miracle (K.E.T.). J.P.L. was funded by National Institutes of Health (T32 CA 009599) and the MD Anderson Cancer Center support grant (P30 CA016672).

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Author notes

  1. Ayush T. Raman & Ming Tang

    Present address: Broad Institute of MIT and Harvard, Cambridge, MA, USA

  2. Jace P. Landry

    Present address: Louisiana State University School of Medicine, New Orleans, LA, USA

  3. Patrick Hwu

    Present address: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

  4. Brandan Wustefeld-Janssens

    Present address: Department of Surgical Oncology, Flint Animal Cancer Center, Colorado State University, Fort Collins, CO, USA

  5. Veena Kochat and Ayush T. Raman authors contributed equally.

Authors and Affiliations

  1. Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Veena Kochat, Sharon M. Landers, Jace P. Landry, Angela D. Bhalla, Min Yi, Emily Z. Keung, Christopher P. Scally, Christina L. Roland, Kelly K. Hunt, Barry W. Feig & Keila E. Torres

  2. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Veena Kochat, Ayush T. Raman, Ming Tang, Jonathan Schulz, Christopher Terranova, Hannah C. Beird, Chia-Chin Wu, Yingda Jiang, **zeng Mao, Jianhua Zhang, P. Andrew Futreal, Kunal Rai & Keila E. Torres

  3. Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX, USA

    Ayush T. Raman & Kunal Rai

  4. Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Yingda Jiang & Keila E. Torres

  5. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Rossana Lazcano, Swati Gite, Davis R. Ingram, Wei-Lien Wang & Alexander J. Lazar

  6. Department of Melanoma Medical Oncology and Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Patrick Hwu

  7. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    John M. Slopis

  8. Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA

    Heather Wilson-Robles & Brandan Wustefeld-Janssens

  9. Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Science, Texas A&M University, College Station, TX, USA

    Dominique J. Wiener

  10. Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Ian E. McCutcheon

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  1. Veena Kochat
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Contributions

VK, KR, and KET designed experiments. VK, SML, and ADB performed experiments. ATR and VK performed the computational analysis and interpretation of the data. VK, ATR, and MT did ChIP-Seq analysis. VK and ATR wrote the manuscript. SML and JPL performed all animal work. ADB and HB analyzed the DNA sequencing data from the cell lines. JS, CT, CCW, and JZ assisted with the data analysis and integration. DI assisted with tissue collection and TMA. SG, RL, WW, and AJL assisted with the TMA analysis. SML generated some of the cell lines. YJ maintained the transgenic zebrafish and mice colonies. EZK, CS, CLR, KKH, BWF, IM, and JS provided patient samples and clinical data. BWJ, DW, and HWR provided canine PNST samples and vetted the diagnosis of the samples. IM, JS, PH, and AF provided clinical and scientific input to the direction of the project. KET and KR supervised the project.

Corresponding authors

Correspondence to Kunal Rai or Keila E. Torres.

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Kochat, V., Raman, A.T., Landers, S.M. et al. Enhancer reprogramming in PRC2-deficient malignant peripheral nerve sheath tumors induces a targetable de-differentiated state. Acta Neuropathol 142, 565–590 (2021). https://doi.org/10.1007/s00401-021-02341-z

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  • DOI: https://doi.org/10.1007/s00401-021-02341-z

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