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

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-Clyde, Stephen T. Magill, William C. Chen, Steve E. Braunstein, Arie Perry, Line Jacques, Alyssa T. Reddy, Melike Pekmezci, Adam R. Abate, Frank McCormick () and David R. Raleigh ()
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Harish N. Vasudevan: University of California San Francisco
Emily Payne: University of California San Francisco
Cyrille L. Delley: University of California San Francisco
S. John Liu: University of California San Francisco
Kanish Mirchia: University of California San Francisco
Matthew J. Sale: University of California San Francisco
Sydney Lastella: University of California San Francisco
Maria Sacconi Nunez: University of California San Francisco
Calixto-Hope G. Lucas: Johns Hopkins University
Charlotte D. Eaton: University of California San Francisco
Tim Casey-Clyde: University of California San Francisco
Stephen T. Magill: Northwestern University
William C. Chen: University of California San Francisco
Steve E. Braunstein: University of California San Francisco
Arie Perry: University of California San Francisco
Line Jacques: University of California San Francisco
Alyssa T. Reddy: 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

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-44755-9

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