Cellular mechanisms of heterogeneity in NF2-mutant schwannoma

Christine Chiasson-MacKenzie, Jeremie Vitte, Ching-Hui Liu, Emily A. Wright, Elizabeth A. Flynn, Shannon L. Stott, Marco Giovannini and Andrea I. McClatchey ()
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Christine Chiasson-MacKenzie: 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
Emily A. Wright: Harvard Medical School
Elizabeth A. Flynn: Harvard Medical School
Shannon L. Stott: 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

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37226-0

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