<i>PTEN</i> and <i>NF1</i> Inactivation in Schwann Cells Produces a Severe Phenotype in the Peripheral Nervous System That Promotes the Development and Malignant Progression of Peripheral Nerve Sheath Tumors

Keng, Vincent W.; Rahrmann, Eric P.; Watson, Adrienne L.; Tschida, Barbara R.; Moertel, Christopher L.; Jessen, Walter J.; Rizvi, Tilat A.; Collins, Margaret H.; Ratner, Nancy; Largaespada, David A.

doi:10.1158/0008-5472.can-11-4092

Cited by 77 publications

(83 citation statements)

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“…For example, PI3K–mTOR signalling is enhanced in Nf1 -mutant astrocytes and MPNSTs 90,91 . PI3K–AKT signalling downstream of Rras2 has a role in the initiation of neurofibromas 92 ; activation of the PI3K pathway through loss of Pten in mice promotes the transformation of Nf1 -driven neurofibromas to MPNSTs 93 . Sustained activation of AKT in MPNST cells requires calcium and calmodulin 94 .…”

Section: Neurofibromin Regulation and Signallingmentioning

confidence: 99%

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

2015

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Neurofibromatosis type 1 (NF1) is a common genetic disorder that predisposes affected individuals to tumours. The NF1 gene encodes a RAS GTPase-activating protein called neurofibromin and is one of several genes that (when mutant) affect RAS–MAPK signalling, causing related diseases collectively known as RASopathies. Several RASopathies, beyond NF1, are cancer predisposition syndromes. Somatic NF1 mutations also occur in 5–10% of human sporadic cancers and may contribute to resistance to therapy. To highlight areas for investigation in RASopathies and sporadic tumours with NF1 mutations, we summarize current knowledge of NF1 disease, the NF1 gene and neurofibromin, neurofibromin signalling pathways and recent developments in NF1 therapeutics.

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Section: Neurofibromin Regulation and Signallingmentioning

confidence: 99%

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

2015

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“…Importantly, phosphatase and tensin homolog ( Pten) and neurofibromatosis 1 ( Nf1 ) were amongst the many candidate genes identified in this screen that tended to be co-mutated in the same PNSTs. Pten -regulated pathways have been shown to be major tumor suppressive barriers to PNST progression in Schwann cells in the context of Nf1 loss [26]. Recently, it has also been shown that PTEN and EGFR both play important roles in the initiation of PNSTs [27].…”

Section: Mouse Models Of Cancermentioning

confidence: 99%

“…This modeled the co-occurrence of Pten and Nf1 found in PNSTs derived from SB mutagenesis. The loss of both Nf1 and Pten in Schwann cells lead to the rapid onset of high grade PNSTs [26]. …”

Section: Mouse Models Of Cancermentioning

confidence: 99%

“…To continue this progress, new mouse models driven by these genes must be developed. Engineered mouse models of several types of cancer including liver cancer [23–25], and neurofibroma/malignant peripheral nerve sheath tumor [26, 27], and glioma [28] that may prove useful for therapeutic testing have been developed. The methods used to generate these models may inform the development of other useful cancer mouse models driven by the genes identified in forward genetic screens.…”

Section: Introductionmentioning

confidence: 99%

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Mouse models of cancer: Sleeping Beauty transposons for insertional mutagenesis screens and reverse genetic studies

Tschida

Largaespada

Keng

2014

Seminars in Cell & Developmental Biology

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The genetic complexity and heterogeneity of cancer has posed a problem in designing rationally targeted therapies effective in a large proportion of human cancer. Genomic characterization of many cancer types has provided a staggering amount of data that needs to be interpreted to further our understanding of this disease. Forward genetic screening in mice using Sleeping Beauty (SB) based insertional mutagenesis is an effective method for candidate cancer gene discovery that can aid in distinguishing driver from passenger mutations in human cancer. This system has been adapted for unbiased screens to identify drivers of multiple cancer types. These screens have already identified hundreds of candidate cancer-promoting mutations. These can be used to develop new mouse models for further study, which may prove useful for therapeutic testing. SB technology may also hold the key for rapid generation of reverse genetic mouse models of cancer, and has already been used to model glioblastoma and liver cancer.

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“…With the development of numerous accurate small-animal (genetically engineered mouse; GEM) models of NF1-associated nervous system tumors (table 1), [8][9][10][11][12][13][14][15][16][17][18] the creation of the NF Clinical Trials Consortium, 19 and the establishment of response criteria for NF1 clinical trials, 20 the stage has been set for the discovery and validation of promising therapeutic strategies and their translation to people affected with NF1. However, despite these advances, there are currently no effective therapies, which likely reflects the striking biological and clinical heterogeneity inherent to this condition.…”

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confidence: 99%

Eliminating barriers to personalized medicine

Gutmann

2014

Neurology

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With the emergence of high-throughput discovery platforms, robust preclinical small-animal models, and efficient clinical trial pipelines, it is becoming possible to envision a time when the treatment of human neurologic diseases will become personalized. The emergence of precision medicine will require the identification of subgroups of patients most likely to respond to specific biologically based therapies. This stratification only becomes possible when the determinants that contribute to disease heterogeneity become more fully elucidated. This review discusses the defining factors that underlie disease heterogeneity relevant to the potential for individualized brain tumor (optic pathway glioma) treatments arising in the common single-gene cancer predisposition syndrome, neurofibromatosis type 1 (NF1). In this regard, NF1 is posited as a model genetic condition to establish a workable paradigm for actualizing precision therapeutics for other neurologic disorders. Neurology ® 2014;83:463-471 GLOSSARY cAMP 5 cyclic adenosine monophosphate; GEM 5 genetically engineered mouse; GWAS 5 genome-wide association studies; mTOR 5 mammalian target of rapamycin; NF1 5 neurofibromatosis type 1; NSC 5 neural stem cell; OPG 5 optic pathway glioma; PA 5 pilocytic astrocytoma; RGC 5 retinal ganglion cell.Neurofibromatosis type 1 (NF1) is one of the most common monogenic disorders in which affected individuals develop benign and malignant tumors.1 NF1 impacts 1:2,500 people worldwide, and individuals with NF1 are prone to the development of peripheral (neurofibromas, malignant peripheral nerve sheath tumors) and central (optic pathway glioma, malignant glioma) nervous system tumors.2,3 Similar to other autosomal dominant cancer predisposition syndromes, 4,5 people with NF1 start life with a germline mutation in one copy of the NF1 tumor suppressor gene; however, tumors require somatic (acquired) inactivation of the remaining functional NF1 allele, leading to complete loss of NF1 expression in specific cell types.6,7 For example, complete Nf1 gene inactivation in neuroglial 8,9 or Schwann cell 10,11 progenitors is required for murine optic glioma or neurofibroma formation, respectively.With the development of numerous accurate small-animal (genetically engineered mouse; GEM) models of NF1-associated nervous system tumors ( the stage has been set for the discovery and validation of promising therapeutic strategies and their translation to people affected with NF1. However, despite these advances, there are currently no effective therapies, which likely reflects the striking biological and clinical heterogeneity inherent to this condition. This review uses NF1-associated brain tumors (optic glioma) as an illustrative platform to discuss the barriers and challenges to developing and implementing effective targeted therapies.NF1-ASSOCIATED OPTIC PATHWAY GLIOMA NF1-associated optic pathway gliomas (NF1-OPGs) are largely pediatric tumors typically arising in children younger than 7 years of age. 21,22 As such, 15%-20% of child...

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PTEN and NF1 Inactivation in Schwann Cells Produces a Severe Phenotype in the Peripheral Nervous System That Promotes the Development and Malignant Progression of Peripheral Nerve Sheath Tumors

Cited by 77 publications

References 23 publications

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

Mouse models of cancer: Sleeping Beauty transposons for insertional mutagenesis screens and reverse genetic studies

Eliminating barriers to personalized medicine

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