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Article ; Online: The RASopathies: Biology, genetics and therapeutic options.

Longo, Jody Fromm / Carroll, Steven L

2021 Volume 153, Page(s) 305–341

Abstract: The RASopathies are a group of genetic diseases in which the Ras/MAPK signaling pathway is inappropriately activated as a result of mutations in genes encoding proteins within this pathway. As their causative mutations have been identified, this group of ...

Abstract	The RASopathies are a group of genetic diseases in which the Ras/MAPK signaling pathway is inappropriately activated as a result of mutations in genes encoding proteins within this pathway. As their causative mutations have been identified, this group of diseases has expanded to include neurofibromatosis type 1 (NF1), Legius syndrome, Noonan syndrome, CBL syndrome, Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, gingival fibromatosis and capillary malformation-arteriovenous malformation syndrome. Many of these genetic disorders share clinical features in common such as abnormal facies, short stature, varying degrees of cognitive impairment, cardiovascular abnormalities, skeletal abnormalities and a predisposition to develop benign and malignant neoplasms. Others are more dissimilar, even though their mutations are in the same gene that is mutated in a different RASopathy. Here, we describe the clinical features of each RASopathy and contrast them with the other RASopathies. We discuss the genetics of these disorders, including the causative mutations for each RASopathy, the impact that these mutations have on the function of an individual protein and how this dysregulates the Ras/MAPK signaling pathway. As several of these individual disorders are genetically heterogeneous, we also consider the different genes that can be mutated to produce disease with the same phenotype. We also discuss how our growing understanding of dysregulated Ras/MAPK signaling had led to the development of new therapeutic agents and what work will be critically important in the future to improve the lives of patients with RASopathies.
MeSH term(s)	Biology ; Failure to Thrive/genetics ; Humans ; Mutation ; Neoplasms ; Noonan Syndrome/genetics ; ras Proteins/genetics ; ras Proteins/metabolism
Chemical Substances	ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2021-08-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	127-2
ISSN	2162-5557 ; 0065-230X
ISSN (online)	2162-5557
ISSN	0065-230X
DOI	10.1016/bs.acr.2021.07.007
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Article ; Online: The Role of R-Ras Proteins in Normal and Pathologic Migration and Morphologic Change.

Weber, Shannon M / Carroll, Steven L

The American journal of pathology

2021 Volume 191, Issue 9, Page(s) 1499–1510

Abstract: The contributions that the R-Ras subfamily [R-Ras, R-Ras2/teratocarcinoma 21 (TC21), and M-Ras] of small GTP-binding proteins make to normal and aberrant cellular functions have historically been poorly understood. However, this has begun to change with ... ...

Abstract	The contributions that the R-Ras subfamily [R-Ras, R-Ras2/teratocarcinoma 21 (TC21), and M-Ras] of small GTP-binding proteins make to normal and aberrant cellular functions have historically been poorly understood. However, this has begun to change with the realization that all three R-Ras subfamily members are occasionally mutated in Noonan syndrome (NS), a RASopathy characterized by the development of hematopoietic neoplasms and abnormalities affecting the immune, cardiovascular, and nervous systems. Consistent with the abnormalities seen in NS, a host of new studies have implicated R-Ras proteins in physiological and pathologic changes in cellular morphology, adhesion, and migration in the cardiovascular, immune, and nervous systems. These changes include regulating the migration and homing of mature and immature immune cells, vascular stabilization, clotting, and axonal and dendritic outgrowth during nervous system development. Dysregulated R-Ras signaling has also been linked to the pathogenesis of cardiovascular disease, intellectual disabilities, and human cancers. This review discusses the structure and regulation of R-Ras proteins and our current understanding of the signaling pathways that they regulate. It explores the phenotype of NS patients and their implications for the R-Ras subfamily functions. Next, it covers recent discoveries regarding physiological and pathologic R-Ras functions in key organ systems. Finally, it discusses how R-Ras signaling is dysregulated in cancers and mechanisms by which this may promote neoplasia.
MeSH term(s)	Animals ; Cell Movement/physiology ; Humans ; Noonan Syndrome/genetics ; Noonan Syndrome/metabolism ; Signal Transduction/physiology ; ras Proteins/metabolism
Chemical Substances	RRAS protein, human (EC 3.6.1.-) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2021-06-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2021.05.008
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Article ; Online: Inhibition of Erb-B2 Receptor Tyrosine Kinase 3 and Associated Regulatory Pathways Potently Impairs Malignant Peripheral Nerve Sheath Tumor Proliferation and Survival.

Black, Laurel E / Longo, Jody F / Anderson, Joshua C / Carroll, Steven L

The American journal of pathology

2023 Volume 193, Issue 9, Page(s) 1298–1318

Abstract: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, currently untreatable Schwann cell-derived neoplasms with hyperactive mitogen-activated protein kinase and mammalian target of rapamycin signaling pathways. To identify potential ... ...

Abstract	Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, currently untreatable Schwann cell-derived neoplasms with hyperactive mitogen-activated protein kinase and mammalian target of rapamycin signaling pathways. To identify potential therapeutic targets, previous studies used genome-scale shRNA screens that implicated the neuregulin-1 receptor erb-B2 receptor tyrosine kinase 3 (erbB3) in MPNST proliferation and/or survival. The current study shows that erbB3 is commonly expressed in MPNSTs and MPNST cell lines and that erbB3 knockdown inhibits MPNST proliferation and survival. Kinomic and microarray analyses of Schwann and MPNST cells implicate Src- and erbB3-mediated calmodulin-regulated signaling as key pathways. Consistent with this, inhibition of upstream (canertinib, sapitinib, saracatinib, and calmodulin) and parallel (AZD1208) signaling pathways involving mitogen-activated protein kinase and mammalian target of rapamycin reduced MPNST proliferation and survival. ErbB inhibitors (canertinib and sapitinib) or erbB3 knockdown in combination with Src (saracatinib), calmodulin [trifluoperazine (TFP)], or proviral integration site of Moloney murine leukemia kinase (AZD1208) inhibition even more effectively reduces proliferation and survival. Drug inhibition enhances an unstudied calmodulin-dependent protein kinase IIα phosphorylation site in an Src-dependent manner. The Src family kinase inhibitor saracatinib reduces both basal and TFP-induced erbB3 and calmodulin-dependent protein kinase IIα phosphorylation. Src inhibition (saracatinib), like erbB3 knockdown, prevents these phosphorylation events; and when combined with TFP, it even more effectively reduces proliferation and survival compared with monotherapy. These findings implicate erbB3, calmodulin, proviral integration site of Moloney murine leukemia kinases, and Src family members as important therapeutic targets in MPNSTs and demonstrate that combinatorial therapies targeting critical MPNST signaling pathways are more effective.
MeSH term(s)	Humans ; Mice ; Animals ; Neurofibrosarcoma ; Receptor, ErbB-2/metabolism ; Receptor, ErbB-2/therapeutic use ; Nerve Sheath Neoplasms/drug therapy ; Nerve Sheath Neoplasms/genetics ; Nerve Sheath Neoplasms/metabolism ; Calmodulin/metabolism ; Calmodulin/pharmacology ; Calmodulin/therapeutic use ; Sirolimus/pharmacology ; Cell Proliferation ; TOR Serine-Threonine Kinases/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Leukemia ; Cell Line, Tumor ; Mammals/metabolism
Chemical Substances	AZD1208 ; Receptor, ErbB-2 (EC 2.7.10.1) ; Calmodulin ; Sirolimus (W36ZG6FT64) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2023-06-14
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2023.05.016
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Article ; Online: The Molecular and Morphologic Structures That Make Saltatory Conduction Possible in Peripheral Nerve.

Carroll, Steven L

Journal of neuropathology and experimental neurology

2017 Volume 76, Issue 4, Page(s) 255–257

Abstract: Saltatory conduction is the process by which action potentials are rapidly and efficiently propagated along myelinated axons. In the peripheral nervous system, saltatory conduction is made possible by a series of morphologically and molecularly distinct ... ...

Abstract	Saltatory conduction is the process by which action potentials are rapidly and efficiently propagated along myelinated axons. In the peripheral nervous system, saltatory conduction is made possible by a series of morphologically and molecularly distinct subdomains in both axons and their associated myelinating Schwann cells. This review briefly summarizes current knowledge on the molecular structure and physiology of the node of Ranvier and adjacent regions of the axoglial unit in peripheral nerve.
MeSH term(s)	Animals ; Axons/physiology ; Humans ; Nerve Fibers, Myelinated/physiology ; Neural Conduction/physiology ; Neurons/metabolism ; Neurons/physiology ; Neurons/ultrastructure ; Peripheral Nerves/metabolism ; Peripheral Nerves/physiology ; Peripheral Nerves/ultrastructure ; Schwann Cells/physiology ; Schwann Cells/ultrastructure
Language	English
Publishing date	2017--01
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	3088-0
ISSN	1554-6578 ; 0022-3069
ISSN (online)	1554-6578
ISSN	0022-3069
DOI	10.1093/jnen/nlx013
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Ui II Zs.194: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)

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Article ; Online: LPAR1 and aberrantly expressed LPAR3 differentially promote the migration and proliferation of malignant peripheral nerve sheath tumor cells.

Doutt, Shannon Weber / Longo, Jody Fromm / Carroll, Steven L

Glia

2022 Volume 71, Issue 3, Page(s) 742–757

Abstract: Schwann cell-derived neoplasms known as malignant peripheral nerve sheath tumors (MPNSTs) are the most common malignancy and the leading cause of death in individuals with neurofibromatosis Type 1. Using genome-scale shRNA screens, we have previously ... ...

Abstract	Schwann cell-derived neoplasms known as malignant peripheral nerve sheath tumors (MPNSTs) are the most common malignancy and the leading cause of death in individuals with neurofibromatosis Type 1. Using genome-scale shRNA screens, we have previously found evidence suggesting that lysophosphatidic acid receptors (LPARs) are essential for MPNST proliferation and/or survival. Here, we examine the expression and mutational status of all six LPA receptors in MPNSTs, assess the role that individual LPA receptors play in MPNST physiology and examine their ability to activate key neurofibromin-regulated signaling cascades. We found that human Schwann cells express LPAR1 and LPAR6, while MPNST cells express predominantly LPAR1 and LPAR3. Whole exome sequencing of 16 MPNST cell lines showed no evidence of mutations in any LPAR genes or ENPP2, a gene encoding a major LPA biosynthetic enzyme. Oleoyl-LPA, an LPA variant with an unsaturated side chain, promoted MPNST cell proliferation and migration. LPAR1 knockdown ablated the promigratory effect of LPA, while LPAR3 knockdown decreased proliferation. Inhibition of R-Ras signaling with a doxycycline-inducible dominant negative (DN) R-Ras mutant, which inhibits both R-Ras and R-Ras2, blocked LPA's promigratory effect. In contrast, DN R-Ras did not affect migration induced by neuregulin-1β (NRG1β), suggesting that LPA and NRG1β promote MPNST migration via distinct pathways. LPA-induced migration was also inhibited by Y27632, an inhibitor of the ROCK1/2 kinases that mediate R-Ras effects in MPNSTs. Thus, LPAR1 and aberrantly expressed LPAR3 mediate distinct effects in MPNSTs. These receptors and the signaling pathways that they regulate are potentially useful therapeutic targets in MPNSTs.
MeSH term(s)	Humans ; Cell Line, Tumor ; Cell Proliferation/genetics ; Nerve Sheath Neoplasms/genetics ; Nerve Sheath Neoplasms/pathology ; Nerve Sheath Neoplasms/therapy ; Neurofibrosarcoma ; Receptors, Lysophosphatidic Acid/genetics ; rho-Associated Kinases
Chemical Substances	LPAR1 protein, human ; Receptors, Lysophosphatidic Acid ; rho-Associated Kinases (EC 2.7.11.1) ; ROCK1 protein, human (EC 2.7.11.1) ; LPAR3 protein, human
Language	English
Publishing date	2022-11-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	639414-0
ISSN	1098-1136 ; 0894-1491
ISSN (online)	1098-1136
ISSN	0894-1491
DOI	10.1002/glia.24308
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Article ; Online: The Challenge of Cancer Genomics in Rare Nervous System Neoplasms: Malignant Peripheral Nerve Sheath Tumors as a Paradigm for Cross-Species Comparative Oncogenomics.

Carroll, Steven L

The American journal of pathology

2016 Volume 186, Issue 3, Page(s) 464–477

Abstract: Comprehensive genomic analyses of common nervous system cancers provide new insights into their pathogenesis, diagnosis, and treatment. Although analogous studies of rare nervous system tumors are needed, there are major barriers to performing such ... ...

Abstract	Comprehensive genomic analyses of common nervous system cancers provide new insights into their pathogenesis, diagnosis, and treatment. Although analogous studies of rare nervous system tumors are needed, there are major barriers to performing such studies. Cross-species comparative oncogenomics, identifying driver mutations in mouse cancer models and validating them in human tumors, is a promising alternative. Although still in its infancy, this approach is being applied to malignant peripheral nerve sheath tumors (MPNSTs), rare Schwann cell-derived malignancies that occur sporadically, after radiotherapy, and in neurofibromatosis type 1. Studies of human neurofibromatosis type 1-associated tumors suggest that NF1 tumor suppressor loss in Schwann cells triggers cell-autonomous and intercellular changes, resulting in development of benign neurofibromas; subsequent neurofibroma-MPNST progression is caused by aberrant growth factor signaling and mutations affecting the p16(INK4A)-cyclin D1-CDK4-Rb and p19(ARF)-Mdm2-p53 cell cycle pathways. Mice with Nf1, Trp53, and/or Cdkn2a mutations that overexpress the Schwann cell mitogen neuregulin-1 or overexpress the epidermal growth factor receptor validate observations in human tumors and, to various degrees, model human tumorigenesis. Genomic analyses of MPNSTs arising in neuregulin-1 and epidermal growth factor receptor-overexpressing mice and forward genetic screens with Sleeping Beauty transposons implicate additional signaling cascades in MPNST pathogenesis. These studies confirm the utility of mouse models for MPNST driver gene discovery and provide new insights into the complexity of MPNST pathogenesis.
MeSH term(s)	Animals ; Cell Cycle ; Cell Transformation, Neoplastic ; Disease Models, Animal ; Genomics ; Humans ; Mice ; Mutation ; Nervous System Neoplasms/genetics ; Nervous System Neoplasms/pathology ; Neurilemmoma/genetics ; Neurilemmoma/pathology ; Neurofibroma/genetics ; Neurofibroma/pathology ; Neurofibromatosis 1/genetics ; Neurofibromatosis 1/pathology ; Schwann Cells/pathology ; Signal Transduction/genetics
Language	English
Publishing date	2016-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2015.10.023
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Article ; Online: Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells.

Longo, Jody Fromm / Brosius, Stephanie N / Carroll, Steven L

Journal of visualized experiments : JoVE

2021 , Issue 174

Abstract: The development of new drugs that precisely target key proteins in human cancers is fundamentally altering cancer therapeutics. However, before these drugs can be used, their target proteins must be validated as therapeutic targets in specific cancer ... ...

Abstract	The development of new drugs that precisely target key proteins in human cancers is fundamentally altering cancer therapeutics. However, before these drugs can be used, their target proteins must be validated as therapeutic targets in specific cancer types. This validation is often performed by knocking out the gene encoding the candidate therapeutic target in a genetically engineered mouse (GEM) model of cancer and determining what effect this has on tumor growth. Unfortunately, technical issues such as embryonic lethality in conventional knockouts and mosaicism in conditional knockouts often limit this approach. To overcome these limitations, an approach to ablating a floxed embryonic lethal gene of interest in short-term cultures of malignant peripheral nerve sheath tumors (MPNSTs) generated in a GEM model was developed. This paper describes how to establish a mouse model with the appropriate genotype, derive short-term tumor cultures from these animals, and then ablate the floxed embryonic lethal gene using an adenoviral vector that expresses Cre recombinase and enhanced green fluorescent protein (eGFP). Purification of cells transduced with adenovirus using fluorescence-activated cell sorting (FACS) and the quantification of the effects that gene ablation exerts on cellular proliferation, viability, the transcriptome, and orthotopic allograft growth is then detailed. These methodologies provide an effective and generalizable approach to identifying and validating therapeutic targets in vitro and in vivo. These approaches also provide a renewable source of low-passage tumor-derived cells with reduced in vitro growth artifacts. This allows the biological role of the targeted gene to be studied in diverse biologic processes such as migration, invasion, metastasis, and intercellular communication mediated by the secretome.
MeSH term(s)	Alleles ; Animals ; Cell Proliferation ; Cell Transformation, Neoplastic ; Genes, Lethal ; Mice ; Nerve Sheath Neoplasms ; Neurofibrosarcoma
Language	English
Publishing date	2021-08-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/62740
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Article ; Online: Salinomycin targets the genome of radioresistant cells in glioblastomas.

Carroll, Steven L / Longo, Jody Fromm

Neuro-oncology

2019 Volume 22, Issue 2, Page(s) 167–168

MeSH term(s)	DNA Replication ; Glioblastoma ; Homologous Recombination ; Humans ; Ionophores ; Pyrans
Chemical Substances	Ionophores ; Pyrans ; salinomycin (62UXS86T64)
Language	English
Publishing date	2019-11-26
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	2028601-6
ISSN	1523-5866 ; 1522-8517
ISSN (online)	1523-5866
ISSN	1522-8517
DOI	10.1093/neuonc/noz224
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Zs.A 5307: Show issues

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Article ; Online: Genetic Profiling and Genome-Scale Dropout Screening to Identify Therapeutic Targets in Mouse Models of Malignant Peripheral Nerve Sheath Tumor.

Turner-Ivey, Brittany / Longo, Jody Fromm / Jenkins, Dorea P / Guest, Stephen T / Carroll, Steven L

Journal of visualized experiments : JoVE

2023 , Issue 198

Abstract: Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are derived from Schwann cells or their precursors. In patients with the tumor susceptibility syndrome neurofibromatosis type 1 (NF1), MPNSTs are the most common malignancy and the leading cause of death. ...

Abstract	Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are derived from Schwann cells or their precursors. In patients with the tumor susceptibility syndrome neurofibromatosis type 1 (NF1), MPNSTs are the most common malignancy and the leading cause of death. These rare and aggressive soft-tissue sarcomas offer a stark future, with 5-year disease-free survival rates of 34-60%. Treatment options for individuals with MPNSTs are disappointingly limited, with disfiguring surgery being the foremost treatment option. Many once-promising therapies such as tipifarnib, an inhibitor of Ras signaling, have failed clinically. Likewise, phase II clinical trials with erlotinib, which targets the epidermal growth factor (EFGR), and sorafenib, which targets the vascular endothelial growth factor receptor (VEGF), platelet-derived growth factor receptor (PDGF), and Raf, in combination with standard chemotherapy, have also failed to produce a response in patients. In recent years, functional genomic screening methods combined with genetic profiling of cancer cell lines have proven useful for identifying essential cytoplasmic signaling pathways and the development of target-specific therapies. In the case of rare tumor types, a variation of this approach known as cross-species comparative oncogenomics is increasingly being used to identify novel therapeutic targets. In cross-species comparative oncogenomics, genetic profiling and functional genomics are performed in genetically engineered mouse (GEM) models and the results are then validated in the rare human specimens and cell lines that are available. This paper describes how to identify candidate driver gene mutations in human and mouse MPNST cells using whole exome sequencing (WES). We then describe how to perform genome-scale shRNA screens to identify and compare critical signaling pathways in mouse and human MPNST cells and identify druggable targets in these pathways. These methodologies provide an effective approach to identifying new therapeutic targets in a variety of human cancer types.
MeSH term(s)	Humans ; Animals ; Mice ; Neurofibrosarcoma ; Vascular Endothelial Growth Factor A ; Epidermal Growth Factor ; Neurofibromatosis 1 ; Sarcoma ; Disease Models, Animal
Chemical Substances	Vascular Endothelial Growth Factor A ; Epidermal Growth Factor (62229-50-9)
Language	English
Publishing date	2023-08-25
Publishing country	United States
Document type	Journal Article ; Video-Audio Media ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/65430
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Article ; Online: Parsing out reality from genetically engineered mouse models of neurologic diseases.

Carroll, Steven L

Brain research bulletin

2012 Volume 88, Issue 1, Page(s) 1–2

MeSH term(s)	Animals ; Disease Models, Animal ; Genetic Engineering ; Humans ; Mice ; Mice, Neurologic Mutants ; Nervous System Diseases/genetics ; Periodicals as Topic
Language	English
Publishing date	2012-05-01
Publishing country	United States
Document type	Editorial ; Introductory Journal Article
ZDB-ID	197620-5
ISSN	1873-2747 ; 0361-9230
ISSN (online)	1873-2747
ISSN	0361-9230
DOI	10.1016/j.brainresbull.2012.04.004
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