Spatial Gene-Expression Profiling Unveils Immuno-oncogenic Programs of NF1-Associated Peripheral Nerve Sheath Tumor Progression.

Autor:	Mitchell DK; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana., Burgess B; Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, Indiana.; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana., White EE; Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, Indiana.; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana., Smith AE; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana., Sierra Potchanant EA; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana., Mang H; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana., Hickey BE; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana., Lu Q; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana., Qian S; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana., Bessler W; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana., Li X; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana., Jiang L; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana., Brewster K; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana., Temm C; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana., Horvai A; Department of Pathology and Laboratory Medicine, University of California San Francisco, San Francisco, California., Albright EA; Department of Clinical Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana., Fishel ML; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana.; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana., Pratilas CA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Angus SP; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana.; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana.; IU Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana., Clapp DW; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana.; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.; IU Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana., Rhodes SD; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana.; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.; IU Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana.; Division of Pediatric Hematology/Oncology/Stem Cell Transplant, Indiana University School of Medicine, Indianapolis, Indiana.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Mar 01; Vol. 30 (5), pp. 1038-1053.
DOI:	10.1158/1078-0432.CCR-23-2548
Abstrakt:	Purpose: Plexiform neurofibromas (PNF) are benign peripheral nerve sheath tumors (PNST) associated with neurofibromatosis type 1 (NF1). Despite similar histologic appearance, these neoplasms exhibit diverse evolutionary trajectories, with a subset progressing to malignant peripheral nerve sheath tumor (MPNST), the leading cause of premature death in individuals with NF1. Malignant transformation of PNF often occurs through the development of atypical neurofibroma (ANF) precursor lesions characterized by distinct histopathologic features and CDKN2A copy-number loss. Although genomic studies have uncovered key driver events promoting tumor progression, the transcriptional changes preceding malignant transformation remain poorly defined. Experimental Design: Here we resolve gene-expression profiles in PNST across the neurofibroma-to-MPNST continuum in NF1 patients and mouse models, revealing early molecular features associated with neurofibroma evolution and transformation. Results: Our findings demonstrate that ANF exhibit enhanced signatures of antigen presentation and immune response, which are suppressed as malignant transformation ensues. MPNST further displayed deregulated survival and mitotic fidelity pathways, and targeting key mediators of these pathways, CENPF and BIRC5, disrupted the growth and viability of human MPNST cell lines and primary murine Nf1-Cdkn2a-mutant Schwann cell precursors. Finally, neurofibromas contiguous with MPNST manifested distinct alterations in core oncogenic and immune surveillance programs, suggesting that early molecular events driving disease progression may precede histopathologic evidence of malignancy. Conclusions: If validated prospectively in future studies, these signatures may serve as molecular diagnostic tools to augment conventional histopathologic diagnosis by identifying neurofibromas at high risk of undergoing malignant transformation, facilitating risk-adapted care. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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