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- Title
Functional interactions between neurofibromatosis tumor suppressors underlie Schwann cell tumor de-differentiation and treatment resistance.
- Authors
Vasudevan, Harish N.; Payne, Emily; Delley, Cyrille L.; John Liu, S.; Mirchia, Kanish; Sale, Matthew J.; Lastella, Sydney; Nunez, Maria Sacconi; Lucas, Calixto-Hope G.; Eaton, Charlotte D.; Casey-Clyde, Tim; Magill, Stephen T.; Chen, William C.; Braunstein, Steve E.; Perry, Arie; Jacques, Line; Reddy, Alyssa T.; Pekmezci, Melike; Abate, Adam R.; McCormick, Frank
- 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. The molecular mechanisms underlying malignant transformation of the Schwann lineage in Schwann cell tumours remain to be explored. Here, the authors suggest that NF2 inactivation leads to PAK activation leading to NF1-mutant Schwann cell tumour de-differentiation and resistance to selumetinib.
- Subjects
PAKISTAN; SCHWANNOMAS; NEUROFIBROMATOSIS; TUMOR treatment; SCHWANN cells; PERIPHERAL nervous system; CELL transformation
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-44755-9