RAS/MEK–Independent Gene Expression Reveals BMP2-Related Malignant Phenotypes in the <i>Nf1</i>-Deficient MPNST

Sun, Duxin; Haddad, Ramsi; Kraniak, Janice M.; Horne, Steven D.; Tainsky, Michael A.

doi:10.1158/1541-7786.mcr-12-0593

Cited by 12 publications

(17 citation statements)

References 59 publications

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“…A recent in vitro study confirmed our original finding that MAF expression is low in ST88-14 NF1 mutant MPNST cells relative to normal human Schwann cells (24), and that SOX9 is elevated (41). MAF expression is also reduced in prostate cancer (42).…”

Section: Discussionsupporting

confidence: 67%

“…MAF expression is also reduced in prostate cancer (42). We found that levels of MAF are very low in all tested MPNST cell lines, including sporadic MPNST cells (24), possibly accounting for the fact that siRNA targeting NF1 in a sporadic (non-NF1 mutant) MPNST cell line did not alter MAF expression (41). Our finding that the NF1-GRD regulates MAF expression implies that activation of one or more Ras proteins suppresses MAF .…”

Section: Discussionmentioning

confidence: 93%

“…Our finding that the NF1-GRD regulates MAF expression implies that activation of one or more Ras proteins suppresses MAF . In NF1 MPNST cells, MAF was not normalized by NRAS siRNA (41); other Ras proteins (e.g. K- or H-Ras) may regulate MAF expression.…”

Section: Discussionmentioning

confidence: 99%

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MAF mediates crosstalk between Ras-MAPK and mTOR signaling in NF1

et al. 2014

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Mutations in the neurofibromatosis type 1 (NF1 tumor suppressor gene are common in cancer, and can cause resistance to therapy. Using transcriptome analysis we identified MAF as an NF1 regulated transcription factor, and verified MAF regulation through RAS/MAPK/AP-1 signaling in malignant peripheral nerve sheath tumor (MPNST) cell lines. MAF was also downregulated in human MPNST. Acute re-expression of MAF promoted expression of glial differentiation markers in MPNST cells in vitro, decreased self-renewal of embryonic precursors and transiently affected tumor cell phenotypes in vitro by increasing MPNST cell death and reducing metabolic activity and anchorage independent growth. Paradoxically, chronic MAF overexpression enhanced MPNST cell tumor growth in vivo, correlating with elevated pS6 in vitro and in vivo. RAD001 blocked MAF-mediated tumor growth, and MAF regulated the mTOR pathway through DEPTOR. MAPK inhibition with NF1 loss of function is predicted to show limited efficacy due to reactivation of mTOR signaling via MAF.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 93%

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MAF mediates crosstalk between Ras-MAPK and mTOR signaling in NF1

et al. 2014

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“…Human NF1-associated MPNST cell lines NF90.8 and ST88-14 were provided by Dr Michael Tainsky (Wayne University, Detroit, MI), T265-2C was obtained from Dr Steven Porcelli (Albert Einstein College of Medicine, Bronx, NY), and sNF96.2 was purchased from ATCC (Manassas, VA) [15, 16]. MPNST cells were maintained in RPMI 1640 medium (Sigma) containing 10% of fetal bovine serum (BenchMarck, Gemini Bio-Products, West Sacramento, CA) and 1% penicillin- streptomycin (Invitrogen Life Technologies, Carlsbad, CA) at 37°C in an humidified 5% CO 2 atmosphere.…”

Section: Methodsmentioning

confidence: 99%

Preclinical evaluation of the combination of mTOR and proteasome inhibitors with radiotherapy in malignant peripheral nerve sheath tumors

Yamashita

Baía

et al. 2014

J Neurooncol

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About one half of malignant peripheral nerve sheath tumors (MPNST) have Neurofibromin 1 (NF1) mutations. NF1 is a tumor suppressor gene essential for negative regulation of RAS signaling. Survival for MPNST patients is poor and we sought to identify an effective combination therapy. Starting with the mTOR inhibitors rapamycin and everolimus, we screened for synergy in 542 FDA approved compounds using MPNST cells with a native NF1 loss in both alleles. We further analyzed the cell cycle and signal transduction. In vivo growth effects of the drug combination with local radiation therapy were assessed in MPNST xenografts. The synergistic combination of mTOR inhibitors with bortezomib yielded a reduction in MPNST cell proliferation. The combination of mTOR inhibitors and bortezomib also enhanced the anti-proliferative effect of radiation in vitro. In vivo, the combination of mTOR inhibitor (everolimus) and bortezomib with radiation therapy decreased tumor growth and proliferation, and augmented apoptosis. The combination of approved mTOR and proteasome inhibitors with radiation showed a significant reduction of tumor growth in an animal model and should be investigated and optimized further for MPNST therapy.

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“…Neurofibromatosis type 1 disease (NF1; Online Mendelian Inheritance in Man/OMIM—database #162200) is a rare chronic neurological disorder caused by a deficient autosomal dominant genetic background, which affects 1 in 3000 live births [1]. Alterations in the tumor suppressor gene neurofibromin (NF1) enhance expression of the Ras signaling pathway, which is involved in the evolution of many cancers [2].…”

Section: Introductionmentioning

confidence: 99%

Gene signature associated with benign neurofibroma transformation to malignant peripheral nerve sheath tumors

et al. 2017

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Benign neurofibromas, the main phenotypic manifestations of the rare neurological disorder neurofibromatosis type 1, degenerate to malignant tumors associated to poor prognosis in about 10% of patients. Despite efforts in the field of (epi)genomics, the lack of prognostic biomarkers with which to predict disease evolution frustrates the adoption of appropriate early therapeutic measures. To identify potential biomarkers of malignant neurofibroma transformation, we integrated four human experimental studies and one for mouse, using a gene score-based meta-analysis method, from which we obtained a score-ranked signature of 579 genes. Genes with the highest absolute scores were classified as promising disease biomarkers. By grouping genes with similar neurofibromatosis-related profiles, we derived panels of potential biomarkers. The addition of promoter methylation data to gene profiles indicated a panel of genes probably silenced by hypermethylation. To identify possible therapeutic treatments, we used the gene signature to query drug expression databases. Trichostatin A and other histone deacetylase inhibitors, as well as cantharidin and tamoxifen, were retrieved as putative therapeutic means to reverse the aberrant regulation that drives to malignant cell proliferation and metastasis. This in silico prediction corroborated reported experimental results that suggested the inclusion of these compounds in clinical trials. This experimental validation supported the suitability of the meta-analysis method used to integrate several sources of public genomic information, and the reliability of the gene signature associated to the malignant evolution of neurofibromas to generate working hypotheses for prognostic and drug-responsive biomarkers or therapeutic measures, thus showing the potential of this in silico approach for biomarker discovery.

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RAS/MEK–Independent Gene Expression Reveals BMP2-Related Malignant Phenotypes in the Nf1-Deficient MPNST

Cited by 12 publications

References 59 publications

MAF mediates crosstalk between Ras-MAPK and mTOR signaling in NF1

MAF mediates crosstalk between Ras-MAPK and mTOR signaling in NF1

Preclinical evaluation of the combination of mTOR and proteasome inhibitors with radiotherapy in malignant peripheral nerve sheath tumors

Gene signature associated with benign neurofibroma transformation to malignant peripheral nerve sheath tumors

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