B-cell lymphoma presenting as multiple nerve sheath tumors.
Ontology highlight
ABSTRACT:
SUBMITTER: Milton J
PROVIDER: S-EPMC5523469 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of death in neurofibromatosis type 1 (NF1) patients. Current treatment modalities have been largely unsuccessful in improving MPNST patient survival, making the identification of new therapeutic targets urgent. In this study, we found that interference with Usp9X, a deubiquitinating enzyme which is overexpressed in nervous system tumors, or Mcl-1, an anti-apoptotic member of the Bcl-2 family whose degradation is regulated by Usp9X, causes rapid death in human MPNST cell lines. Although both Usp9X and Mcl-1 knockdown elicited some features of apoptosis, broad spectrum caspase inhibition was ineffective in preventing knockdown-induced MPNST cell death suggesting that caspase-independent death pathways were also activated. Ultrastructural examination of MPNST cells following either Usp9X interference or pharmacological inhibition showed extensive cytoplasmic vacuolization and swelling of endoplasmic reticulum (ER) and mitochondria most consistent with paraptotic cell death. Finally, the Usp9X pharmacological inhibitor WP1130 significantly reduced human MPNST growth and induced tumor cell death in an in vivo xenograft model. In total, these findings indicate that Usp9X and Mcl-1 play significant roles in maintaining human MPNST cell viability and that pharmacological inhibition of Usp9X deubiquitinase activity could be a therapeutic target for MPNST treatment.
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Project description:Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas typically developing in the context of neurofibromatosis type 1 (NF-1). With the exception of surgical resection, these tumors are resistant to all current therapies, and unresectable, recurrent, or metastatic tumors are considered incurable. Preclinical studies have identified several novel candidate molecular targets for therapeutic intervention, but, to date, targeted therapies have proven ineffective. Recent studies have identified recurrent mutations in polycomb repressive complex 2 (PRC2) core components, embryonic ectoderm development protein (EED) and suppressor of zeste 12 homolog (SUZ12), in MPNST. These mutations result in global loss of the histone H3 lysine 27 trimethylation epigenetic mark, normally deposited by PRC2, and subsequent gain in acetylation at this residue. This altered chromatin state has been shown to promote MPNST malignancy; however, acetylation at this residue sensitizes MPNSTs to BRD4 and bromodomain and extra-terminal domain inhibition. Interestingly, the catalytic component of PRC2, enhancer of zeste homolog 2 (EZH2), is not mutated in MPNST, hinting that a noncanonical, PRC2-independent function of EZH2 may play a role in this cancer. This review examines the pathobiology of MPNST, the contribution of PRC2 subunits to this process, and the prospects for PRC2-related therapies for this cancer. IMPLICATIONS: Identification of mutations in the PRC2 components EED and SUZ12 in the majority of MPNSTs may imply noncanonical oncogenic activities of the intact component, EZH2, and provide new opportunities for therapeutic intervention.
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Project description:TP53 is the most frequently mutated tumor suppressor gene in human cancer, with nearly 50% of all tumors exhibiting a loss-of-function mutation. To further elucidate the genetic pathways involving TP53 and cancer, we have exploited the zebrafish, a powerful vertebrate model system that is amenable to whole-genome forward-genetic analysis and synthetic-lethal screens. Zebrafish lines harboring missense mutations in the tp53 DNA-binding domain were identified by using a target-selected mutagenesis strategy. Homozygous mutant fish from two of these lines were viable and exhibited mutations similar to those found in human cancers (tp53(N168K) and tp53(M214K)). Although homozygous tp53(N168K) mutants were temperature-sensitive and suppressed radiation-induced apoptosis only at 37 degrees C, cells in the tp53(M214K) embryos failed to undergo apoptosis in response to gamma radiation at both 28 and 37 degrees C. Unlike wild-type control embryos, irradiated tp53(M214K) embryos also failed to up-regulate p21 and did not arrest at the G(1)/S checkpoint. Beginning at 8.5 months of age, 28% of tp53(M214K) mutant fish developed malignant peripheral nerve sheath tumors. In addition to providing a model for studying the molecular pathogenic pathways of malignant peripheral nerve sheath tumors, these mutant zebrafish lines provide a unique platform for modifier screens to identify genetic mutations or small molecules that affect tp53-related pathways, including apoptosis, cell-cycle delay, and tumor suppression.
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Project description:Nerve sheath tumors (NSTs) are characterized by neoplastic proliferation of Schwann cells, perineurial cells, endoneurial and/or epineurial fibroblasts. Diagnosis of NST is often challenging, particularly in distinguishing malignant NST (MNST) from other soft tissue sarcomas, or sometimes between low-grade MNST and benign NST. Recent studies in human pathology have demonstrated loss of trimethylation at lysine 27 of histone 3 (H3K27me3) in a subset of MNSTs using immunohistochemistry. Loss of H3K27me3 expression is rare in other high-grade sarcomas and also appears to be useful in distinguishing benign and low-grade MNSTs from high-grade subsets. In our retrospective study, we performed H3K27me3 immunohistochemistry in 68 canine tumors previously diagnosed as NST. We detected loss of H3K27me3 expression in 25% (n = 17) of all canine NST, including one neurofibroma, whereas 49% (n = 33) of tumors had mosaic loss of expression and 26% (n = 18) retained expression. No statistically significant differences were found between H3K27me3 expression, histopathological features of tumors, and their immunoreactivity for Sox10, claudin-1, GFAP, and Ki67. Because the classification of canine NST is not yet fully established and its correlation with the prognosis and clinical course of the disease is lacking, prospective studies with possible genetic analyses are needed to assess the true diagnostic value of H3K27me3 loss in canine NST.
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Project description:PurposeBET bromodomain inhibitors have emerged as a promising therapy for numerous cancer types in preclinical studies, including neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumor (MPNST). However, potential mechanisms underlying resistance to these inhibitors in different cancers are not completely understood. In this study, we explore new strategy to overcome BET inhibitor resistance in MPNST.Experimental Design: Through modeling tumor evolution by studying genetic changes underlying the development of MPNST, a lethal sarcoma with no effective medical treatment, we identified a targetable addiction to BET bromodomain family member BRD4 in MPNST. This served as a controlled model system to delineate mechanisms of sensitivity and resistance to BET bromodomain inhibitors in this disease.ResultsHere, we show that a malignant progression-associated increase in BRD4 protein levels corresponds to partial sensitivity to BET inhibition in MPNST. Strikingly, genetic depletion of BRD4 protein levels synergistically sensitized MPNST cells to diverse BET inhibitors in culture and in vivo.ConclusionsCollectively, MPNST sensitivity to combination genetic and pharmacologic inhibition of BRD4 revealed the presence of a unique addiction to BRD4 in MPNST. Our discovery that a synthetic lethality exists between BET inhibition and reduced BRD4 protein levels nominates MPNST for the investigation of emerging therapeutic interventions such as proteolysis-targeting chimeras (PROTACs) that simultaneously target bromodomain activity and BET protein abundance.
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Project description:Peripheral nerve sheath tumors (PNSTs) include schwannomas, neurofibromas (NFs), and plexiform neurofibromas (PNFs), among others. While they are benign tumors, according to their biological behavior, some have the potential for malignant degeneration, mainly PNFs. The specific factors contributing to the more aggressive behavior of some PNSTs compared to others are not precisely known. Considering that lipid homeostasis plays a crucial role in fibrotic/inflammatory processes and in several cancers, we hypothesized that the lipid asset was also unbalanced in this group of nerve tumors. Through untargeted lipidomics, NFs presented a significant increase in ceramide, phosphatidylcholine, and Vitamin A ester. PNFs displayed a marked decrease in 34 out of 50 lipid class analyzed. An increased level of ether- and oxidized-triacylglycerols was observed; phosphatidylcholines were reduced. After sphingolipidomic analysis, we observed six sphingolipid classes. Ceramide and dihydroceramides were statistically increased in NFs. All the glycosylated species appeared reduced in NFs, but increased in PNFs. Our findings suggested that different subtypes of PNSTs presented a specific modulation in the lipidic profile. The untargeted and targeted lipidomic approaches, which were not applied until now, contribute to better clarifying bioactive lipid roles in PNS natural history to highlight disease molecular features and pathogenesis.
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Project description:Neurofibromatosis 1 is a hereditary syndrome characterized by the development of numerous benign neurofibromas, a small subset of which progress to malignant peripheral nerve sheath tumors (MPNSTs). To better understand the genetic basis for MPNSTs, we performed genome-wide or targeted sequencing on 50 cases. Sixteen MPNSTs but none of the neurofibromas tested were found to have somatic mutations in SUZ12, implicating it as having a central role in malignant transformation.
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Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that arise in connective tissue surrounding peripheral nerves. They occur sporadically in a subset of patients with neurofibromatosis type 1 (NF1). MPNSTs are highly aggressive, therapeutically resistant, and typically fatal. Using comparative transcriptome analysis, we identified CXCR4, a G-protein-coupled receptor, as highly expressed in mouse models of NF1-deficient MPNSTs, but not in nontransformed precursor cells. The chemokine receptor CXCR4 and its ligand, CXCL12, promote MPNST growth by stimulating cyclin D1 expression and cell-cycle progression through PI3-kinase (PI3K) and ?-catenin signaling. Suppression of CXCR4 activity either by shRNA or pharmacological inhibition decreases MPNST cell growth in culture and inhibits tumorigenesis in allografts and in spontaneous genetic mouse models of MPNST. We further demonstrate conservation of these activated molecular pathways in human MPNSTs. Our findings indicate a role for CXCR4 in NF1-associated MPNST development and identify a therapeutic target.
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Project description:The characterization of peripheral nerve sheath tumors is challenging. The purpose here was to investigate the diagnostic value of quantitative proton MR spectroscopy at 3T for the characterization of peripheral nerve sheath tumors as benign or malignant, compared with PET.Twenty participants with 24 peripheral nerve sheath tumors underwent MR spectroscopy by use of a point-resolved sequence (TE, 135 ms). Six voxels were placed in 4 histologically proven malignant peripheral nerve sheath tumors and 22 voxels in 20 benign peripheral nerve sheath tumors (9 histologically proven, 11 with documented stability). The presence or absence of a trimethylamine signal was evaluated, the trimethylamine concentration estimated by use of phantom replacement methodology, and the trimethylamine fraction relative to Cr measured. MR spectroscopy results for benign and malignant peripheral nerve sheath tumors were compared by use of a Mann-Whitney test, and concordance or discordance with PET findings was recorded.In all malignant tumors and in 9 of 18 benign peripheral nerve sheath tumors, a trimethylamine peak was detected, offering the presence of trimethylamine as a sensitive (100%), but not specific (50%), marker of malignant disease. Trimethylamine concentrations (2.2 ± 2.8 vs 6.6 ± 5.8 institutional units; P < .049) and the trimethylamine fraction (27 ± 42 vs 88 ± 22%; P < .012) were lower in benign than malignant peripheral nerve sheath tumors. A trimethylamine fraction threshold of 50% resulted in 100% sensitivity (95% CI, 58.0%-100%) and 72.2% (95% CI, 59.5%-75%) specificity for distinguishing benign from malignant disease. MR spectroscopy and PET results were concordant in 12 of 16 cases, (2 false-positive results for MR spectroscopy and PET each).Quantitative measurement of trimethylamine concentration by use of MR spectroscopy is feasible in peripheral nerve sheath tumors and shows promise as a method for the differentiation of benign and malignant lesions. Trimethylamine presence within a peripheral nerve sheath tumor is a sensitive marker of malignant disease, but quantitative measurement of trimethylamine content is required to improve specificity.
| S-EPMC4086645 | biostudies-literature
Project description:BACKGROUND:Malignant peripheral nerve sheath tumors (MPNSTs) are rare yet highly aggressive soft tissue sarcomas. Children with neurofibromatosis type 1 (NF1) have a 10% lifetime risk for development of MPNST. Prognosis remains poor and survival seems worse for NF1 patients. METHODS:This narrative review highlights current practices and pitfalls in the management of MPNST in pediatric NF1 patients. RESULTS:Preoperative diagnostics can be challenging, but PET scans have shown to be useful tools. More recently, functional MRI holds promise as well. Surgery remains the mainstay treatment for these patients, but careful planning is needed to minimize postoperative morbidity. Functional reconstructions can play a role in improving functional status. Radiotherapy can be administered to enhance local control in selected cases, but care should be taken to minimize radiation effects as well as reduce the risk of secondary malignancies. The exact role of chemotherapy has yet to be determined. Reports on the efficacy of chemotherapy vary as some report lower effects in NF1 populations. Promisingly, survival seems to ameliorate in the last few decades and response rates of chemotherapy may increase in NF1 populations when administering it as part of standard of care. However, in metastasized disease, response rates remain poor. New systemic therapies are therefore desperately warranted and multiple trials are currently investigating the role of drugs. Targeted drugs are nevertheless not yet included in first line treatment. CONCLUSION:Both research and clinical efforts benefit from multidisciplinary approaches with international collaborations in this rare malignancy.
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