IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-44755-9.html
   My bibliography  Save this article

Functional interactions between neurofibromatosis tumor suppressors underlie Schwann cell tumor de-differentiation and treatment resistance

Author

Listed:
  • Harish N. Vasudevan

    (University of California San Francisco
    University of California San Francisco)

  • Emily Payne

    (University of California San Francisco
    University of California San Francisco)

  • Cyrille L. Delley

    (University of California San Francisco)

  • S. John Liu

    (University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Kanish Mirchia

    (University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Matthew J. Sale

    (University of California San Francisco)

  • Sydney Lastella

    (University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Maria Sacconi Nunez

    (University of California San Francisco
    University of California San Francisco)

  • Calixto-Hope G. Lucas

    (Johns Hopkins University)

  • Charlotte D. Eaton

    (University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Tim Casey-Clyde

    (University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Stephen T. Magill

    (Northwestern University)

  • William C. Chen

    (University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Steve E. Braunstein

    (University of California San Francisco)

  • Arie Perry

    (University of California San Francisco
    University of California San Francisco)

  • Line Jacques

    (University of California San Francisco)

  • Alyssa T. Reddy

    (University of California San Francisco
    University of California San Francisco)

  • Melike Pekmezci

    (University of California San Francisco)

  • Adam R. Abate

    (University of California San Francisco)

  • Frank McCormick

    (University of California San Francisco)

  • David R. Raleigh

    (University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

Abstract

Schwann cell tumors are the most common cancers of the peripheral nervous system and can arise in patients with neurofibromatosis type-1 (NF-1) or neurofibromatosis type-2 (NF-2). Functional interactions between NF1 and NF2 and broader mechanisms underlying malignant transformation of the Schwann lineage are unclear. Here we integrate bulk and single-cell genomics, biochemistry, and pharmacology across human samples, cell lines, and mouse allografts to identify cellular de-differentiation mechanisms driving malignant transformation and treatment resistance. We find DNA methylation groups of Schwann cell tumors can be distinguished by differentiation programs that correlate with response to the MEK inhibitor selumetinib. Functional genomic screening in NF1-mutant tumor cells reveals NF2 loss and PAK activation underlie selumetinib resistance, and we find that concurrent MEK and PAK inhibition is effective in vivo. These data support a de-differentiation paradigm underlying malignant transformation and treatment resistance of Schwann cell tumors and elucidate a functional link between NF1 and NF2.

Suggested Citation

  • Harish N. Vasudevan & Emily Payne & Cyrille L. Delley & S. John Liu & Kanish Mirchia & Matthew J. Sale & Sydney Lastella & Maria Sacconi Nunez & Calixto-Hope G. Lucas & Charlotte D. Eaton & Tim Casey-, 2024. "Functional interactions between neurofibromatosis tumor suppressors underlie Schwann cell tumor de-differentiation and treatment resistance," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44755-9
    DOI: 10.1038/s41467-024-44755-9
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-44755-9
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-44755-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. David Capper & David T. W. Jones & Martin Sill & Volker Hovestadt & Daniel Schrimpf & Dominik Sturm & Christian Koelsche & Felix Sahm & Lukas Chavez & David E. Reuss & Annekathrin Kratz & Annika K. We, 2018. "DNA methylation-based classification of central nervous system tumours," Nature, Nature, vol. 555(7697), pages 469-474, March.
    2. Stephen T. Magill & Harish N. Vasudevan & Kyounghee Seo & Javier E. Villanueva-Meyer & Abrar Choudhury & S. John Liu & Melike Pekmezci & Sarah Findakly & Stephanie Hilz & Sydney Lastella & Benjamin De, 2020. "Multiplatform genomic profiling and magnetic resonance imaging identify mechanisms underlying intratumor heterogeneity in meningioma," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Maria Pouyiourou & Bianca N. Kraft & Timothy Wohlfromm & Michael Stahl & Boris Kubuschok & Harald Löffler & Ulrich T. Hacker & Gerdt Hübner & Lena Weiss & Michael Bitzer & Thomas Ernst & Philipp Schüt, 2023. "Nivolumab and ipilimumab in recurrent or refractory cancer of unknown primary: a phase II trial," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    2. Xi Lu & Naga Prathyusha Maturi & Malin Jarvius & Irem Yildirim & Yonglong Dang & Linxuan Zhao & Yuan Xie & E-Jean Tan & Pengwei Xing & Rolf Larsson & Mårten Fryknäs & Lene Uhrbom & Xingqi Chen, 2022. "Cell-lineage controlled epigenetic regulation in glioblastoma stem cells determines functionally distinct subgroups and predicts patient survival," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Claire Vinel & Gabriel Rosser & Loredana Guglielmi & Myrianni Constantinou & Nicola Pomella & Xinyu Zhang & James R. Boot & Tania A. Jones & Thomas O. Millner & Anaelle A. Dumas & Vardhman Rakyan & Je, 2021. "Comparative epigenetic analysis of tumour initiating cells and syngeneic EPSC-derived neural stem cells in glioblastoma," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    4. Marc Cicero Schubert & Stella Judith Soyka & Amr Tamimi & Emanuel Maus & Julian Schroers & Niklas Wißmann & Ekin Reyhan & Svenja Kristin Tetzlaff & Yvonne Yang & Robert Denninger & Robin Peretzke & Ca, 2024. "Deep intravital brain tumor imaging enabled by tailored three-photon microscopy and analysis," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    5. Josefine Radke & Elisa Schumann & Julia Onken & Randi Koll & Güliz Acker & Bohdan Bodnar & Carolin Senger & Sascha Tierling & Markus Möbs & Peter Vajkoczy & Anna Vidal & Sandra Högler & Petra Kodajova, 2022. "Decoding molecular programs in melanoma brain metastases," Nature Communications, Nature, vol. 13(1), pages 1-24, December.
    6. David R. Ghasemi & Konstantin Okonechnikov & Anne Rademacher & Stephan Tirier & Kendra K. Maass & Hanna Schumacher & Piyush Joshi & Maxwell P. Gold & Julia Sundheimer & Britta Statz & Ahmet S. Rifaiog, 2024. "Compartments in medulloblastoma with extensive nodularity are connected through differentiation along the granular precursor lineage," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    7. Konstantin Okonechnikov & Aylin Camgöz & Owen Chapman & Sameena Wani & Donglim Esther Park & Jens-Martin Hübner & Abhijit Chakraborty & Meghana Pagadala & Rosalind Bump & Sahaana Chandran & Katerina K, 2023. "3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    8. Felix K. F. Kommoss & Anne-Sophie Chong & Anne-Laure Chong & Elke Pfaff & David T. W. Jones & Laura S. Hiemcke-Jiwa & Lennart A. Kester & Uta Flucke & Manfred Gessler & Daniel Schrimpf & Felix Sahm & , 2023. "Genomic characterization of DICER1-associated neoplasms uncovers molecular classes," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    9. Grayson A. Herrgott & James M. Snyder & Ruicong She & Tathiane M. Malta & Thais S. Sabedot & Ian Y. Lee & Jacob Pawloski & Guilherme G. Podolsky-Gondim & Karam P. Asmaro & Jiaqi Zhang & Cara E. Cannel, 2023. "Detection of diagnostic and prognostic methylation-based signatures in liquid biopsy specimens from patients with meningiomas," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    10. Min Kyung Lee & Nasim Azizgolshani & Ze Zhang & Laurent Perreard & Fred W. Kolling & Lananh N. Nguyen & George J. Zanazzi & Lucas A. Salas & Brock C. Christensen, 2024. "Associations in cell type-specific hydroxymethylation and transcriptional alterations of pediatric central nervous system tumors," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    11. Ting Xie & Adi Danieli-Mackay & Mariachiara Buccarelli & Mariano Barbieri & Ioanna Papadionysiou & Q. Giorgio D’Alessandris & Claudia Robens & Nadine Übelmesser & Omkar Suhas Vinchure & Liverana Laure, 2024. "Pervasive structural heterogeneity rewires glioblastoma chromosomes to sustain patient-specific transcriptional programs," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    12. Jie Yang & Qianghu Wang & Ze-Yan Zhang & Lihong Long & Ravesanker Ezhilarasan & Jerome M. Karp & Aristotelis Tsirigos & Matija Snuderl & Benedikt Wiestler & Wolfgang Wick & Yinsen Miao & Jason T. Huse, 2022. "DNA methylation-based epigenetic signatures predict somatic genomic alterations in gliomas," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    13. María-Jesús Lobón-Iglesias & Mamy Andrianteranagna & Zhi-Yan Han & Céline Chauvin & Julien Masliah-Planchon & Valeria Manriquez & Arnault Tauziede-Espariat & Sandrina Turczynski & Rachida Bouarich-Bou, 2023. "Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    14. Philipp Jurmeister & Stefanie Glöß & Renée Roller & Maximilian Leitheiser & Simone Schmid & Liliana H. Mochmann & Emma Payá Capilla & Rebecca Fritz & Carsten Dittmayer & Corinna Friedrich & Anne Thiem, 2022. "DNA methylation-based classification of sinonasal tumors," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    15. Marie Duhamel & Lauranne Drelich & Maxence Wisztorski & Soulaimane Aboulouard & Jean-Pascal Gimeno & Nina Ogrinc & Patrick Devos & Tristan Cardon & Michael Weller & Fabienne Escande & Fahed Zairi & Cl, 2022. "Spatial analysis of the glioblastoma proteome reveals specific molecular signatures and markers of survival," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    16. Christy W. LaFlamme & Cassandra Rastin & Soham Sengupta & Helen E. Pennington & Sophie J. Russ-Hall & Amy L. Schneider & Emily S. Bonkowski & Edith P. Almanza Fuerte & Talia J. Allan & Miranda Perez-G, 2024. "Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    17. N. Shukla & M. F. Levine & G. Gundem & D. Domenico & B. Spitzer & N. Bouvier & J. E. Arango-Ossa & D. Glodzik & J. S. Medina-Martínez & U. Bhanot & J. Gutiérrez-Abril & Y. Zhou & E. Fiala & E. Stockfi, 2022. "Feasibility of whole genome and transcriptome profiling in pediatric and young adult cancers," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    18. Norman L. Lehman & Nathalie Spassky & Müge Sak & Amy Webb & Cory T. Zumbar & Aisulu Usubalieva & Khaled J. Alkhateeb & Joseph P. McElroy & Kirsteen H. Maclean & Paolo Fadda & Tom Liu & Vineela Gangala, 2022. "Astroblastomas exhibit radial glia stem cell lineages and differential expression of imprinted and X-inactivation escape genes," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    19. Yuanyuan Chen & Reka Toth & Sara Chocarro & Dieter Weichenhan & Joschka Hey & Pavlo Lutsik & Stefan Sawall & Georgios T. Stathopoulos & Christoph Plass & Rocio Sotillo, 2022. "Club cells employ regeneration mechanisms during lung tumorigenesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    20. Francesco Antonica & Lucia Santomaso & Davide Pernici & Linda Petrucci & Giuseppe Aiello & Alessandro Cutarelli & Luciano Conti & Alessandro Romanel & Evelina Miele & Toma Tebaldi & Luca Tiberi, 2022. "A slow-cycling/quiescent cells subpopulation is involved in glioma invasiveness," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44755-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.