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Cellular mechanisms of heterogeneity in NF2-mutant schwannoma

Author

Listed:
  • Christine Chiasson-MacKenzie

    (Harvard Medical School
    Massachusetts General Hospital, Harvard Medical School)

  • Jeremie Vitte

    (David Geffen School of Medicine at UCLA and Jonsson Comprehensive Cancer Center (JCCC), University of California Los Angeles)

  • Ching-Hui Liu

    (Harvard Medical School
    Massachusetts General Hospital, Harvard Medical School)

  • Emily A. Wright

    (Harvard Medical School
    Massachusetts General Hospital, Harvard Medical School)

  • Elizabeth A. Flynn

    (Harvard Medical School
    Surgical Services, Massachusetts General Hospital, Harvard Medical School)

  • Shannon L. Stott

    (Harvard Medical School
    Surgical Services, Massachusetts General Hospital, Harvard Medical School)

  • Marco Giovannini

    (David Geffen School of Medicine at UCLA and Jonsson Comprehensive Cancer Center (JCCC), University of California Los Angeles)

  • Andrea I. McClatchey

    (Harvard Medical School
    Massachusetts General Hospital, Harvard Medical School)

Abstract

Schwannomas are common sporadic tumors and hallmarks of familial neurofibromatosis type 2 (NF2) that develop predominantly on cranial and spinal nerves. Virtually all schwannomas result from inactivation of the NF2 tumor suppressor gene with few, if any, cooperating mutations. Despite their genetic uniformity schwannomas exhibit remarkable clinical and therapeutic heterogeneity, which has impeded successful treatment. How heterogeneity develops in NF2-mutant schwannomas is unknown. We have found that loss of the membrane:cytoskeleton-associated NF2 tumor suppressor, merlin, yields unstable intrinsic polarity and enables Nf2−/− Schwann cells to adopt distinct programs of ErbB ligand production and polarized signaling, suggesting a self-generated model of schwannoma heterogeneity. We validated the heterogeneous distribution of biomarkers of these programs in human schwannoma and exploited the synchronous development of lesions in a mouse model to establish a quantitative pipeline for studying how schwannoma heterogeneity evolves. Our studies highlight the importance of intrinsic mechanisms of heterogeneity across human cancers.

Suggested Citation

  • Christine Chiasson-MacKenzie & Jeremie Vitte & Ching-Hui Liu & Emily A. Wright & Elizabeth A. Flynn & Shannon L. Stott & Marco Giovannini & Andrea I. McClatchey, 2023. "Cellular mechanisms of heterogeneity in NF2-mutant schwannoma," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37226-0
    DOI: 10.1038/s41467-023-37226-0
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    References listed on IDEAS

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    1. Carlos Carmona-Fontaine & Helen K. Matthews & Sei Kuriyama & Mauricio Moreno & Graham A. Dunn & Maddy Parsons & Claudio D. Stern & Roberto Mayor, 2008. "Contact inhibition of locomotion in vivo controls neural crest directional migration," Nature, Nature, vol. 456(7224), pages 957-961, December.
    2. Xiao Wang & Mokarram Hossain & Ania Bogoslowski & Paul Kubes & Daniel Irimia, 2020. "Chemotaxing neutrophils enter alternate branches at capillary bifurcations," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
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