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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
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    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.
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