Journal article
Oncogenic RABL6A promotes NF1-associated MPNST progression in vivo
Neuro-oncology advances, Vol.4(1), pp.vdac047-vdac047
01/01/2022
DOI: 10.1093/noajnl/vdac047
PMCID: PMC9092646
PMID: 35571990
Abstract
Abstract
Background
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with complex molecular and genetic alterations. Powerful tumor suppressors CDKN2A and TP53 are commonly disrupted along with NF1, a gene that encodes a negative regulator of Ras. Many additional factors have been implicated in MPNST pathogenesis. A greater understanding of critical drivers of MPNSTs is needed to guide more informed targeted therapies for patients. RABL6A is a newly identified driver of MPNST cell survival and proliferation whose in vivo role in the disease is unknown.
Methods
Using CRISPR-Cas9 targeting of Nf1 + Cdkn2a or Nf1 + Tp53 in the mouse sciatic nerve to form de novo MPNSTs, we investigated the biological significance of RABL6A in MPNST development. Terminal tumors were evaluated by western blot, qRT-PCR, and immunohistochemistry.
Results
Mice lacking Rabl6 displayed slower tumor progression and extended survival relative to wildtype animals in both genetic contexts. YAP oncogenic activity was selectively downregulated in Rabl6-null, Nf1 + Cdkn2a lesions whereas loss of RABL6A caused upregulation of the CDK inhibitor, p27, in all tumors. Paradoxically, both models displayed elevated Myc protein and Ki67 staining in terminal tumors lacking RABL6A. In Nf1 + p53 tumors, cellular atypia and polyploidy were evident and increased by RABL6A loss.
Conclusions
These findings demonstrate that RABL6A is required for optimal progression of NF1 mutant MPNSTs in vivo in both Cdkn2a and p53 inactivated settings. However, sustained RABL6A loss may provide selective pressure for unwanted alterations, including increased Myc, cellular atypia, and polyploidy, that ultimately promote a hyper-proliferative tumor phenotype akin to drug-resistant lesions.
Details
- Title: Subtitle
- Oncogenic RABL6A promotes NF1-associated MPNST progression in vivo
- Creators
- Jordan L Kohlmeyer - University of IowaCourtney A Kaemmer - University of IowaJoshua J Lingo - Roy J. and Lucille A. Carver College of MedicineEllen Voigt - Roy J. and Lucille A. Carver College of MedicineMariah R Leidinger - University of IowaGavin R McGivney - Roy J. and Lucille A. Carver College of MedicineAmanda Scherer - University of IowaStacia L Koppenhafer - University of IowaDavid J Gordon - University of IowaPatrick Breheny - University of IowaDavid K Meyerholz - Roy J. and Lucille A. Carver College of MedicineMunir R Tanas - University of IowaRebecca D Dodd - University of IowaDawn E Quelle - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- Neuro-oncology advances, Vol.4(1), pp.vdac047-vdac047
- DOI
- 10.1093/noajnl/vdac047
- PMID
- 35571990
- PMCID
- PMC9092646
- NLM abbreviation
- Neurooncol Adv
- ISSN
- 2632-2498
- eISSN
- 2632-2498
- Grant note
- DOI: 10.13039/100000054, name: National Cancer Institute, award: P30 CA086862; name: National Cancer Institute Neuroendocrine Tumor SPORE, award: P50 CA174521; DOI: 10.13039/100000065, name: National Institute of Neurological Disorders and Stroke, award: R01 NS119322
- Language
- English
- Date published
- 01/01/2022
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Stead Family Department of Pediatrics; Pathology; Biostatistics; Hematology/Oncology; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984303856802771
Metrics
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