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Functional interactions between neurofibromatosis tumor suppressors underlie Schwann cell tumor de-differentiation and treatment resistance.
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; Raleigh, David R.
Afiliação
  • Vasudevan HN; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA. harish.vasudevan@ucsf.edu.
  • Payne E; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA. harish.vasudevan@ucsf.edu.
  • Delley CL; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
  • John Liu S; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
  • Mirchia K; Department of Bioengineering, University of California San Francisco, San Francisco, CA, USA.
  • Sale MJ; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
  • Lastella S; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
  • Nunez MS; Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
  • Lucas CG; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
  • Eaton CD; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
  • Casey-Clyde T; Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
  • Magill ST; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
  • Chen WC; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
  • Braunstein SE; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
  • Perry A; Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
  • Jacques L; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
  • Reddy AT; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
  • Pekmezci M; Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
  • Abate AR; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
  • McCormick F; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
  • Raleigh DR; Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
Nat Commun ; 15(1): 477, 2024 Jan 12.
Article em En | MEDLINE | ID: mdl-38216572
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neurofibromatose 2 / Neurofibromatose 1 / Neurofibromatoses / Neurilemoma Limite: Animals / Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neurofibromatose 2 / Neurofibromatose 1 / Neurofibromatoses / Neurilemoma Limite: Animals / Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos