The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Nancy Ratner - One of the best experts on this subject based on the ideXlab platform.
-
a molecular basis for Neurofibroma associated skeletal manifestations in nf1
Genetics in Medicine, 2020Co-Authors: Andrea M Gross, Eva Dombi, Wade D Clapp, Kwangmin Choi, Katherine E Chaney, Alexander Pemov, Steven D Rhodes, Steven P Angus, Noah Sciaky, Nancy RatnerAbstract:Plexiform Neurofibromas (pNF) develop in children with Neurofibromatosis type 1 (NF1) and can be associated with several skeletal comorbidities. Preclinical mouse studies revealed Nf1 deficiency in osteoprogenitor cells disrupts, in a MEK-dependent manner, pyrophosphate (PPi) homeostasis and skeletal mineralization. The etiology of NF-associated skeletal manifestations remains unknown. We used mouse models of NF1 Neurofibromas to assess bone mineralization of skeletal structures adjacent to tumors. Expression of genes involved in pyrophosphate homeostasis was assessed in mouse and human NF tumors and Schwann cell cultures. We used dual-energy X-ray absorptiometry (DXA) to assess tumor-associated changes in bone mineral density (BMD) in an individual with NF1 following treatment with the MEK inhibitor selumetinib. We detected increased nonmineralized bone surfaces adjacent to tumors in mouse models of NF1 Neurofibromas. Expression of Enpp1, a PPi-generating ectophosphatase, and ANKH, a PPi transporter, was increased in mouse and human Neurofibroma-derived tissues and Schwann cells, respectively. In one patient, tumor-associated reductions in BMD were partially rescued following therapy with selumetinib. Results indicate that NF-associated skeletal pathologies in NF1 are associated with dysregulated pyrophosphate homeostasis in adjacent NF tumors and suggest that treatment of NFs with MEK inhibitors may improve skeletal manifestations of the disease.
-
abstract b32 cxcr3 expressing leukocytes are necessary for Neurofibroma formation in mice
Cancer immunology research, 2020Co-Authors: Jonathan S Fletcher, Walter J. Jessen, Tilat A. Rizvi, Mi-ok Kim, Eva Dombi, Jay Pundavela, Kashish Chetal, Nathan Salomonis, Nancy RatnerAbstract:Plexiform Neurofibroma is a major contributor to morbidity in Neurofibromatosis type I (NF1) patients. Macrophages and mast cells infiltrate Neurofibroma, and data from mouse models implicate these leukocytes in Neurofibroma development. Anti-inflammatory therapy targeting these cell populations has been suggested as a means to prevent Neurofibroma development. Here, we compare gene expression in inflamed nerves from NF1 models that invariably form Neurofibroma to those with inflammation driven by EGFR overexpression, which rarely progresses to Neurofibroma. We find that the chemokine Cxcl10 is uniquely upregulated in NF1 mice that invariably develop Neurofibroma. Global deletion of the Cxcl10 receptor Cxcr3 prevented Neurofibroma development in these Neurofibroma-prone mice. Cxcr3 expression localized to T cells and dendritic cells (DCs) in both inflamed nerves and Neurofibromas. These data support a heretofore unappreciated role for T cells/DCs in Neurofibroma initiation. Citation Format: Jonathan S. Fletcher, Jianqiang Wu, Walter J. Jessen, Jay Pundavela, Eva Dombi, Mi-Ok Kim, Tilat A. Rizvi, Kashish Chetal, Nathan Salomonis, Nancy Ratner. Cxcr3-expressing leukocytes are necessary for Neurofibroma formation in mice [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B32.
-
preclinical assessments of the mek inhibitor pd 0325901 in a mouse model of Neurofibromatosis type 1
PMC, 2015Co-Authors: Edwin Jousma, Tilat A. Rizvi, Mi-ok Kim, Eva Dombi, David Janhofer, Richard Scott Dunn, Andrea R Masters, David R Jones, Timothy P Cripe, Nancy RatnerAbstract:Background Neurofibromatosis type 1 (NF1) is a genetic disorder that predisposes affected individuals to formation of benign Neurofibromas, peripheral nerve tumors that can be associated with significant morbidity. Loss of the NF1 Ras–GAP protein causes increased Ras–GTP, and we previously found that inhibiting MEK signaling downstream of Ras can shrink established Neurofibromas in a genetically engineered murine model. Procedures We studied effects of MEK inhibition using 1.5 mg/kg/day PD-0325901 prior to Neurofibroma onset in the Nf1 flox/flox; Dhh–Cre mouse model. We also treated mice with established tumors at 0.5 and 1.5 mg/kg/day doses of PD-0325901. We monitored tumor volumes using MRI and volumetric measurements, and measured pharmacokinetic and pharmacodynamic endpoints. Results Early administration significantly delayed Neurofibroma development as compared to vehicle controls. When treatment was discontinued Neurofibromas grew, but no rebound effect was observed and Neurofibromas remained significantly smaller than controls. Low dose treatment of mice with PD-0325901 resulted in Neurofibroma shrinkage equivalent to that observed at higher doses. Tumor cell proliferation decreased, although less than at higher doses with drug. Tumor blood vessels per area correlated with tumor shrinkage. Conclusions Neurofibroma development was not prevented by MEK inhibition, beginning at 1 month of age, but tumor size was controlled by early treatment. Moreover, treatment with PD-0325901 at very low doses may shrink Neurofibromas while minimizing toxicity. These studies highlight how genetically engineered mouse models can guide clinical trial design. Pediatr Blood Cancer 2015;62:1709–1716. © 2015 Wiley Periodicals, Inc.
-
pm 18egfr stat3 activates β catenin signaling to drive Neurofibroma initiation in nf1 and plays a role in tumor maintenance
Neuro-oncology, 2014Co-Authors: Nancy Ratner, Edwin Jousma, Kwangmin Choi, Vincent W Keng, Deanna M Patmore, Danhua Fan, Jed K Kendall, Eric B Schwartz, James R Fuchs, Yuanshu ZouAbstract:To identify genes and signaling pathways that drive peripheral nerve tumor initiation and growth beyond the Ras-MAPK pathway we used unbiased insertional mutagenesis screening. We identified Stat3 as a potential driver of Neurofibromatosis type 1 Neurofibroma. Targeted genetic deletion of Stat3 in Schwann cell precursors (SCPs) and Schwann cells (SCs) largely prevented Neurofibroma formation, and self-renewal of tumor initiating cells. Genetic gain- and loss-of-function identified EGFR as the major upstream regulator of P-Stat3 in mouse and human Neurofibroma SCP and in Neurofibroma initiation; IL-6 reinforced EGFR/Jak/Stat signaling. Preclinical tests of a Jak2/Stat3 inhibitor reduced established Neurofibroma growth, supporting an additional role for Stat3 in benign nerve tumor maintenance. Unexpectedly, downstream of Stat3, we identified β-catenin, and β-catenin expression rescued phenotypic effects of Stat3 loss in SCPs. Phosphorylated STAT3 (Y705) and β-catenin were strongly correlated in NF1 human plexiform Neurofibromas. The data support testing of JAK/STAT inhibition and Wnt/ β-catenin pathway inhibition in Neurofibroma therapeutic trials. Supported by: NIH R01 NS28840 to N.R. and NIH P50 NS057531 to N.R. and D.L.), a DAMD New Investigator Award (W81XWH-11-1-0259) and an Ohio State University Comprehensive Cancer Center Pelotonia Idea Grant (to J.W.). The American Cancer Society (IRG-67-003-44) supported J.R.F.
-
preclincial testing of sorafenib and rad001 in the nf flox flox dhhcre mouse model of plexiform Neurofibroma using magnetic resonance imaging
Pediatric Blood & Cancer, 2012Co-Authors: Eva Dombi, Edwin Jousma, Brigitte C. Widemann, Mi-ok Kim, Timothy P Cripe, Scott R Dunn, Aerang Kim, Diana M Lindquist, Beverly Schnell, Nancy RatnerAbstract:Background Neurofibromatosis type 1 (NF1) is an inherited disease predisposing affected patients to variable numbers of benign Neurofibromas. To date there are no effective chemotherapeutic drugs available for this slow growing tumor. Molecularly targeted agents that aim to slow Neurofibroma growth are being tested in clinical trials. So preclinical models for testing potential therapies are urgently needed to prioritize drugs for clinical trials of Neurofibromas. Procedure We used magnetic resonance imaging (MRI) to monitor Neurofibroma development in the Nf1flox/flox;DhhCre mouse model of GEM grade I Neurofibroma. Based on studies implicating mTOR and Raf signaling in NF1 mutant cells, we tested the therapeutic effect of RAD001 and Sorafenib in this model. Mice were scanned to establish growth rate followed by 8 weeks of drug treatment, then re-imaged after the last dose of drug treatment. Tumor volumes were determined by volumetric measurement. Results We found that rate of tumor growth varied among mice, as it does in human patients. RAD001 inhibited its predicted target pS6K, yet there was no significant decrease in the tumor volume in RAD001 treated mice compared to the vehicle control group. Sorafenib inhibited cyclinD1 expression and cell proliferation in tumors, and volumetric measurements identified significant decreases in tumor volume in some mice. Conclusion The data demonstrate that volumetric MRI analysis can be used to monitor the therapeutic effect in the preclinical Neurofibroma drug screening, and suggest that Sorafenib might have clinical activity in some Neurofibromas. Pediatr Blood Cancer 2012; 58: 173–180. © 2011 Wiley Periodicals, Inc.
Eva Dombi - One of the best experts on this subject based on the ideXlab platform.
-
a molecular basis for Neurofibroma associated skeletal manifestations in nf1
Genetics in Medicine, 2020Co-Authors: Andrea M Gross, Eva Dombi, Wade D Clapp, Kwangmin Choi, Katherine E Chaney, Alexander Pemov, Steven D Rhodes, Steven P Angus, Noah Sciaky, Nancy RatnerAbstract:Plexiform Neurofibromas (pNF) develop in children with Neurofibromatosis type 1 (NF1) and can be associated with several skeletal comorbidities. Preclinical mouse studies revealed Nf1 deficiency in osteoprogenitor cells disrupts, in a MEK-dependent manner, pyrophosphate (PPi) homeostasis and skeletal mineralization. The etiology of NF-associated skeletal manifestations remains unknown. We used mouse models of NF1 Neurofibromas to assess bone mineralization of skeletal structures adjacent to tumors. Expression of genes involved in pyrophosphate homeostasis was assessed in mouse and human NF tumors and Schwann cell cultures. We used dual-energy X-ray absorptiometry (DXA) to assess tumor-associated changes in bone mineral density (BMD) in an individual with NF1 following treatment with the MEK inhibitor selumetinib. We detected increased nonmineralized bone surfaces adjacent to tumors in mouse models of NF1 Neurofibromas. Expression of Enpp1, a PPi-generating ectophosphatase, and ANKH, a PPi transporter, was increased in mouse and human Neurofibroma-derived tissues and Schwann cells, respectively. In one patient, tumor-associated reductions in BMD were partially rescued following therapy with selumetinib. Results indicate that NF-associated skeletal pathologies in NF1 are associated with dysregulated pyrophosphate homeostasis in adjacent NF tumors and suggest that treatment of NFs with MEK inhibitors may improve skeletal manifestations of the disease.
-
abstract b32 cxcr3 expressing leukocytes are necessary for Neurofibroma formation in mice
Cancer immunology research, 2020Co-Authors: Jonathan S Fletcher, Walter J. Jessen, Tilat A. Rizvi, Mi-ok Kim, Eva Dombi, Jay Pundavela, Kashish Chetal, Nathan Salomonis, Nancy RatnerAbstract:Plexiform Neurofibroma is a major contributor to morbidity in Neurofibromatosis type I (NF1) patients. Macrophages and mast cells infiltrate Neurofibroma, and data from mouse models implicate these leukocytes in Neurofibroma development. Anti-inflammatory therapy targeting these cell populations has been suggested as a means to prevent Neurofibroma development. Here, we compare gene expression in inflamed nerves from NF1 models that invariably form Neurofibroma to those with inflammation driven by EGFR overexpression, which rarely progresses to Neurofibroma. We find that the chemokine Cxcl10 is uniquely upregulated in NF1 mice that invariably develop Neurofibroma. Global deletion of the Cxcl10 receptor Cxcr3 prevented Neurofibroma development in these Neurofibroma-prone mice. Cxcr3 expression localized to T cells and dendritic cells (DCs) in both inflamed nerves and Neurofibromas. These data support a heretofore unappreciated role for T cells/DCs in Neurofibroma initiation. Citation Format: Jonathan S. Fletcher, Jianqiang Wu, Walter J. Jessen, Jay Pundavela, Eva Dombi, Mi-Ok Kim, Tilat A. Rizvi, Kashish Chetal, Nathan Salomonis, Nancy Ratner. Cxcr3-expressing leukocytes are necessary for Neurofibroma formation in mice [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B32.
-
cxcr3 expressing leukocytes are necessary for Neurofibroma formation in mice
JCI insight, 2019Co-Authors: Walter J. Jessen, Tilat A. Rizvi, Mi-ok Kim, Eva Dombi, Jonathan S Fletcher, Jay Pundavela, Jacob A Miller, Kashish Chetal, Nathan SalomonisAbstract:Plexiform Neurofibroma is a major contributor to morbidity in patients with Neurofibromatosis type I (NF1). Macrophages and mast cells infiltrate Neurofibroma, and data from mouse models implicate these leukocytes in Neurofibroma development. Antiinflammatory therapy targeting these cell populations has been suggested as a means to prevent Neurofibroma development. Here, we compare gene expression in Nf1-mutant nerves, which invariably form Neurofibroma, and show disruption of neuron-glial cell interactions and immune cell infiltration to mouse models, which rarely progresses to Neurofibroma with or without disruption of neuron-glial cell interactions. We find that the chemokine Cxcl10 is uniquely upregulated in NF1 mice that invariably develop Neurofibroma. Global deletion of the CXCL10 receptor Cxcr3 prevented Neurofibroma development in these Neurofibroma-prone mice, and an anti-Cxcr3 antibody somewhat reduced tumor numbers. Cxcr3 expression localized to T cells and DCs in both inflamed nerves and Neurofibromas, and Cxcr3 expression was necessary to sustain elevated macrophage numbers in Nf1-mutant nerves. To our knowledge, these data support a heretofore-unappreciated role for T cells and DCs in Neurofibroma initiation.
-
activity of selumetinib in Neurofibromatosis type 1 related plexiform Neurofibromas
The New England Journal of Medicine, 2016Co-Authors: Eva Dombi, Andrea Baldwin, Leigh Marcus, Michael Fisher, Brian Weiss, Aerang Kim, Patricia Whitcomb, Staci Martin, Lindsey AschbachersmithAbstract:BackgroundEffective medical therapies are lacking for the treatment of Neurofibromatosis type 1–related plexiform Neurofibromas, which are characterized by elevated RAS–mitogen-activated protein kinase (MAPK) signaling. MethodsWe conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had Neurofibromatosis type 1 and inoperable plexiform Neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of Neurofibromatosis type 1–related Neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of plexiform Neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform Neurofibroma. Results...
-
runx1 contributes to Neurofibromatosis type 1 Neurofibroma formation
Oncogene, 2016Co-Authors: Xinyang Zhao, Walter J. Jessen, Mi-ok Kim, Eva Dombi, X Yan, Paul Liu, Gang HuangAbstract:Neurofibromatosis type 1 (NF1) patients are predisposed to Neurofibromas but the driver(s) that contribute to Neurofibroma formation are not fully understood. By cross comparison of microarray gene lists on human Neurofibroma-initiating cells and developed Neurofibroma Schwann cells (SCs) we identified RUNX1 overexpression in human Neurofibroma initiation cells, suggesting RUNX1 might relate to Neurofibroma formation. Immunostaining confirmed RUNX1 protein overexpression in human plexiform Neurofibromas. Runx1 overexpression was confirmed in mouse Schwann cell progenitors (SCPs) and mouse Neurofibromas at the messenger RNA and protein levels. Genetic inhibition of Runx1 expression by small hairpin RNA or pharmacological inhibition of Runx1 function by a Runx1/Cbfβ interaction inhibitor, Ro5-3335, decreased mouse Neurofibroma sphere number in vitro. Targeted genetic deletion of Runx1 in SCs and SCPs delayed mouse Neurofibroma formation in vivo. Mechanistically, loss of Nf1 increased embryonic day 12.5 Runx1+/Blbp+ progenitors that enable tumor formation. These results suggest that Runx1 has an important role in Nf1 Neurofibroma initiation, and inhibition of RUNX1 function might provide a novel potential therapeutic treatment strategy for Neurofibroma patients.
Feng Chun Yang - One of the best experts on this subject based on the ideXlab platform.
-
The Plexiform Neurofibroma Microenvironment
Cancer Microenvironment, 2012Co-Authors: Feng Chun Yang, Karl Staser, D. Wade ClappAbstract:Dynamic interactions between tumorigenic cells and surrounding cells, including immunomodulatory hematopoietic cells, can dictate tumor initiation, progression, and transformation. Hematopoietic-stromal interactions underpin the plexiform Neurofibroma, a debilitating tumor arising in individuals afflicted with Neurofibromatosis type 1 (NF1), a common genetic disorder resulting from mutations in the NF1 tumor suppressor gene. At the tissue level, plexiform Neurofibromas demonstrate a complex microenvironment composed of Schwann cells, fibroblasts, perineural cells, mast cells, secreted collagen, and blood vessels. At the cellular level, specific interactions between these cells engender tumor initiation and progression. In this microenvironment hypothesis, tumorigenic Schwann cells secrete pathological concentrations of stem cell factor, which recruit c-kit expressing mast cells. In turn, activated mast cells release inflammatory effectors stimulating the tumorigenic Schwann cells and their supporting fibroblasts and blood vessels, thus promoting tumor expansion in a feed-forward loop. Bone marrow transplantation experiments in plexiform Neurofibroma mouse models have shown that tumorigenesis requires Nf1 haploinsufficiency in the hematopoietic compartment, suggesting that tumor microenvironments can depend on intricate interactions at both cellular and genetic levels. Overall, our continued understanding of critical tumor-stromal interactions will illuminate novel therapeutic targets, as shown by the first-ever successful medical treatment of a plexiform Neurofibroma by targeted inhibition of the stem cell factor/c-kit axis.
-
pathogenesis of plexiform Neurofibroma tumor stromal hematopoietic interactions in tumor progression
Annual Review of Pathology-mechanisms of Disease, 2012Co-Authors: Karl Staser, Feng Chun Yang, Wade D ClappAbstract:Neurofibromatosis type 1 (NF1) is a genetic disease that results from either heritable or spontaneous autosomal dominant mutations in the NF1 gene. A second-hit mutation precedes the predominant NF1 neoplasms, which include myeloid leukemia, optic glioma, and plexiform Neurofibroma. Despite this requisite NF1 loss of heterozygosity in the tumor cell of origin, nontumorigenic cells contribute to both generalized and specific disease manifestations. In mouse models of plexiform Neurofibroma formation, Nf1 haploinsufficient mast cells promote inflammation, accelerating tumor formation and growth. These recruited mast cells, hematopoietic effector cells long known to permeate Neurofibroma tissue, mediate key mitogenic signals that contribute to vascular ingrowth, collagen deposition, and tumor growth. Thus, the plexiform Neurofibroma microenvironment involves a tumor/stromal interaction with the hematopoietic system that depends, at the molecular level, on a stem cell factor/c-kit-mediated signaling axis. These observations parallel findings in other NF1 disease manifestations and are clearly relevant to medical management of these Neurofibromas.
-
nf1 mast cells induce Neurofibroma like phenotypes through secreted tgf β signaling
Human Molecular Genetics, 2006Co-Authors: Feng Chun Yang, Jin Yuan, Shi Chen, Travis Clegg, Trent Morgan, Selina A Estwick, Waleed Khalaf, Sarah J Burgin, Jeff Travers, Luis F ParadaAbstract:Neurofibromas are common tumors found in Neurofibromatosis type 1 (NF1) patients. These complex tumors are composed of Schwann cells, mast cells, fibroblasts and perineurial cells embedded in collagen that provide a lattice for tumor invasion. Genetic studies demonstrate that in Neurofibromas, nullizygous loss of Nf1 in Schwann cells and haploinsufficiency of Nf1 in non-neuronal cells are required for tumorigenesis. Fibroblasts are a major cellular constituent in Neurofibromas and are a source of collagen that constitutes approximately 50% of the dry weight of the tumor. Here, we show that two of the prevalent heterozygous cells found in Neurofibromas, mast cells and fibroblasts interact directly to contribute to tumor phenotype. Nf1+/- mast cells secrete elevated concentrations of the profibrotic transforming growth factor-beta (TGF-beta). In response to TGF-beta, both murine Nf1+/- fibroblasts and fibroblasts from human Neurofibromas proliferate and synthesize excessive collagen, a hallmark of Neurofibromas. We also establish that the TGF-beta response occurs via hyperactivation of a novel Ras-c-abl signaling pathway. Genetic or pharmacological inhibition of c-abl reverses fibroblast proliferation and collagen synthesis to wild-type levels. These studies identify a novel molecular target to inhibit Neurofibroma formation.
-
Neurofibroma associated growth factors activate a distinct signaling network to alter the function of neurofibromin deficient endothelial cells
Human Molecular Genetics, 2006Co-Authors: Amy M. Munchhof, Hilary White, Laura E. Mead, Theresa R. Krier, Amy Fenoglio, Feng Chun Yang, Jin Yuan, David A. IngramAbstract:Genetic inactivation of tumor suppressor genes initiates human cancers. However, interaction of accessory cells with the tumor-initiating cell within the microenvironment is often required for tumor progression. This paradigm is relevant to understanding Neurofibroma development in Neurofibromatosis type I patients. Somatic inactivation of the Nf1 tumor suppressor gene, which encodes neurofibromin, is necessary but not sufficient to initiate Neurofibroma development. In contrast, Neurofibromas occur with high penetrance in mice in which Nf1 is ablated in Schwann cells in the context of a heterozygous mutant (Nf1+/-) microenvironment. Neurofibromas are highly vascularized, and recent studies suggest that Nf1+/- mice have increased angiogenesis in vivo. However, the function of neurofibromin in human endothelial cells (ECs) and the biochemical mechanism by which neurofibromin regulates neoangiogenesis are not known. Utilizing Nf1+/- mice, primary human ECs and endothelial progenitor cells harvested from NF1 patients, we identified a discrete Ras effector pathway, which alters the proliferation and migration of neurofibromin-deficient ECs in response to Neurofibroma-derived growth factors both in vitro and in vivo. Thus, these studies identify a unique biochemical pathway in Nf1+/- ECs as a potential therapeutic target in the Neurofibroma microenvironment.
-
neurofibromin deficient schwann cells secrete a potent migratory stimulus for nf1 mast cells
Journal of Clinical Investigation, 2003Co-Authors: Feng Chun Yang, David A. Ingram, Hilary White, Laura E. Mead, Nancy Ratner, Shi Chen, Cynthia M Hingtgen, Kelly R Monk, Travis Clegg, Mary Jo WenningAbstract:The NF1 tumor suppressor gene encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras signaling. Mutations in NF1 cause Neurofibromatosis type 1 (NF1). The development of Neurofibromas, which are complex tumors composed of multiple cell types, is a hallmark of NF1. Somatic inactivation of murine Nf1 in Schwann cells is necessary, but not sufficient, to initiate Neurofibroma formation. Neurofibromas occur with high penetrance in mice in which Nf1 is ablated in Schwann cells in the context of a heterozygous mutant (Nf1+/-) microenvironment. Mast cells infiltrate Neurofibromas, where they secrete proteins that can remodel the ECM and initiate angiogenesis. Thus, identification of mechanisms responsible for mast cell migration to tumor microenvironments is important for understanding tumorigenesis and for designing potential therapies. Here, we show that homozygous Nf1 mutant (Nf1-/-) Schwann cells secrete Kit ligand (KitL), which stimulates mast cell migration, and that Nf1+/- mast cells are hypermotile in response to KitL. Furthermore, we link hyperactivation of the Ras-class IA-PI3K-Rac2 pathway to increased Nf1+/- mast cell migration. Thus, these studies identify a novel interaction between Nf1-/- Schwann cells and Nf1+/- mast cells that is likely to be important in Neurofibroma formation.
Margaret R. Wallace - One of the best experts on this subject based on the ideXlab platform.
-
nf1 patient missense variants predict a role for atm in modifying Neurofibroma initiation
Acta Neuropathologica, 2020Co-Authors: Kwangmin Choi, Jose A Cancelas, Paul R Andreassen, Phillip J Dexheimer, Mehdi Keddache, Hilde Brems, Robert J Spinner, Lisa J Martin, Margaret R. WallaceAbstract:In Neurofibromatosis type 1, NF1 gene mutations in Schwann cells (SC) drive benign plexiform Neurofibroma (PNF), and no additional SC changes explain patient-to-patient variability in tumor number. Evidence from twin studies suggests that variable expressivity might be caused by unidentified modifier genes. Whole exome sequencing of SC and fibroblast DNA from the same resected PNFs confirmed biallelic SC NF1 mutations; non-NF1 somatic SC variants were variable and present at low read number. We identified frequent germline variants as possible Neurofibroma modifier genes. Genes harboring variants were validated in two additional cohorts of NF1 patients and by variant burden test. Genes including CUBN, CELSR2, COL14A1, ATR and ATM also showed decreased gene expression in some Neurofibromas. ATM-relevant DNA repair defects were also present in a subset of Neurofibromas with ATM variants, and in some Neurofibroma SC. Heterozygous ATM G2023R or homozygous S707P variants reduced ATM protein expression in heterologous cells. In mice, genetic Atm heterozygosity promoted Schwann cell precursor self-renewal and increased tumor formation in vivo, suggesting that ATM variants contribute to Neurofibroma initiation. We identify germline variants, rare in the general population, overrepresented in NF1 patients with Neurofibromas. ATM and other identified genes are candidate modifiers of PNF pathogenesis.
-
immortalization of human normal and nf1 Neurofibroma schwann cells
Laboratory Investigation, 2016Co-Authors: Lungji Chang, Debbie Neubauer, David Muir, Margaret R. WallaceAbstract:Neurofibromas, which are benign Schwann cell tumors, are the hallmark feature in the autosomal dominant condition Neurofibromatosis 1 (NF1) and are associated with biallelic loss of NF1 gene function. There is a need for effective therapies for Neurofibromas, particularly the larger, plexiform Neurofibromas. Tissue culture is an important tool for research. However, it is difficult to derive enriched human Schwann cell cultures, and most enter replicative senescence after 6-10 passages, impeding cell-based research in NF1. Through exogenous expression of human telomerase reverse transcriptase and murine cyclin-dependent kinase (mCdk4), normal (NF1 wild-type), Neurofibroma-derived Schwann cells heterozygous for NF1 mutation, and Neurofibroma-derived Schwann cells homozygous for NF1 mutation were immortalized, including some matched samples from the same NF1 patient. Initial experiments employed retroviral vectors, while subsequent work utilized lentiviral vectors carrying these genes because of improved efficiency. Expression of both transgenes was required for immortalization. Molecular and immunohistochemical analysis indicated that these cell lines are of Schwann cell lineage and have a range of phenotypes, many of which are consistent with their primary cultures. This is the first report of immortalization and detailed characterization of multiple human NF1 normal nerve and Neurofibroma-derived Schwann cell lines, which will be highly useful research tools to study NF1 and other Schwann tumor biology and conditions.
-
Tumorigenic Properties of Neurofibromin-Deficient Neurofibroma Schwann Cells
The American journal of pathology, 2001Co-Authors: David Muir, Debbie Neubauer, Ingrid T. Lim, Anthony T. Yachnis, Margaret R. WallaceAbstract:Dermal and plexiform Neurofibromas are peripheral nerve sheath tumors that arise frequently in Neurofibromatosis type 1. The goal of the present study was to examine the tumorigenic properties of neurofibromin-deficient human Schwann cells (SCs) that were found to represent a subset of SCs present in approximately half of the total Neurofibromas examined. Highly enriched SC cultures were established from 10 dermal and eight plexiform Neurofibromas by selective subculture using glial growth factor-2 and laminin. These cultures had low tumorigenic potential in classical in vitro assays yet several unique preneoplastic properties were frequently observed, including delayed senescence, a lack of density-limited growth, and a strong propensity to spontaneously form proliferative cell aggregates rich in extracellular matrix. Western blot analysis failed to detect full-length neurofibromin in any of the Neurofibroma SC cultures, indicating that neurofibromin-deficient SCs had a substantial growth advantage. Immunohistochemical staining of the originating tumors showed the majority were comprised principally of neurofibromin-negative SCs, whereas the remainder contained both neurofibromin-negative and neurofibromin-positive SCs. Lastly, engraftment of neurofibromin-deficient SC cultures into the peripheral nerves of scid mice consistently produced persistent Neurofibroma-like tumors with diffuse and often extensive intraneural growth. These findings indicate that neurofibromin-deficient SCs are involved in Neurofibroma formation and, by selective subculture, provide a resource for the development of an in vivo model to further examine the role of these mutant SCs in Neurofibroma histogenesis.
Jose A Cancelas - One of the best experts on this subject based on the ideXlab platform.
-
p2ry14 egfr crosstalk is perturbed by loss of the nf1 tumor suppressor and modulates schwann cell precursor self renewal and Neurofibroma initiation
Social Science Research Network, 2021Co-Authors: Jennifer Patritti Cram, Tilat A. Rizvi, Jose A Cancelas, Robert J Spinner, Shinji Kuninaka, Robert A Coover, Robert F Hennigan, Katherine E Chaney, Eric P Rahrmann, David A LargaespadaAbstract:Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by nerve tumors called Neurofibromas. Expression profiling of human Schwann cells (SCs) and Neurofibroma SC precursors (SCPs) identified enriched P2RY14 expression in Neurofibroma SCPs. We show that genetic and pharmacological inhibition of P2RY14 in human and murine NF1 mutant SCPs reduces SCP self-renewal in vitro. We identified the mechanism of action being, P2RY14 forms a complex with the epidermal growth factor receptor (EGFR) to regulate cAMP and RAS signaling. In vivo, genetic deletion of P2RY14 in NF1 murine model delayed Neurofibroma initiation, reduced cAMP and increased Caveolin 1 ( Cav1 ) expression. In a murine model where EGFR is overexpressed in SCs, genetic deletion of Cav1 increased Neurofibroma initiation. Thus, P2RY14 regulates EGFR signaling, cAMP and Cav1 expression, facilitating SCP self-renewal and Neurofibroma initiation. These gain and loss of function experiments suggest critical roles for P2RY14-EGFR crosstalk perturbed by NF1 tumor suppressor loss.
-
nf1 patient missense variants predict a role for atm in modifying Neurofibroma initiation
Acta Neuropathologica, 2020Co-Authors: Kwangmin Choi, Jose A Cancelas, Paul R Andreassen, Phillip J Dexheimer, Mehdi Keddache, Hilde Brems, Robert J Spinner, Lisa J Martin, Margaret R. WallaceAbstract:In Neurofibromatosis type 1, NF1 gene mutations in Schwann cells (SC) drive benign plexiform Neurofibroma (PNF), and no additional SC changes explain patient-to-patient variability in tumor number. Evidence from twin studies suggests that variable expressivity might be caused by unidentified modifier genes. Whole exome sequencing of SC and fibroblast DNA from the same resected PNFs confirmed biallelic SC NF1 mutations; non-NF1 somatic SC variants were variable and present at low read number. We identified frequent germline variants as possible Neurofibroma modifier genes. Genes harboring variants were validated in two additional cohorts of NF1 patients and by variant burden test. Genes including CUBN, CELSR2, COL14A1, ATR and ATM also showed decreased gene expression in some Neurofibromas. ATM-relevant DNA repair defects were also present in a subset of Neurofibromas with ATM variants, and in some Neurofibroma SC. Heterozygous ATM G2023R or homozygous S707P variants reduced ATM protein expression in heterologous cells. In mice, genetic Atm heterozygosity promoted Schwann cell precursor self-renewal and increased tumor formation in vivo, suggesting that ATM variants contribute to Neurofibroma initiation. We identify germline variants, rare in the general population, overrepresented in NF1 patients with Neurofibromas. ATM and other identified genes are candidate modifiers of PNF pathogenesis.
-
Neurofibroma associated macrophages play roles in tumor growth and response to pharmacological inhibition
Acta Neuropathologica, 2013Co-Authors: Carlos E Prada, Edwin Jousma, Tilat A. Rizvi, Mi-ok Kim, Eva Dombi, Jose A Cancelas, Scott R Dunn, Debra A Mayes, Brian L West, Gideon BollagAbstract:Neurofibromatosis type 1 (NF1) is a common genetic disease that predisposes 30–50 % of affected individuals to develop plexiform Neurofibromas. We found that macrophage infiltration of both mouse and human Neurofibromas correlates with disease progression. Macrophages accounted for almost half of Neurofibroma cells, leading us to hypothesize that nerve macrophages are inflammatory effectors in Neurofibroma development and/or growth. We tested the effects of PLX3397, a dual kit/fms kinase inhibitor that blocks macrophage infiltration, in the Dhh-Cre; Nf1flox/flox mouse model of GEM grade I Neurofibroma. In mice aged 1–4 months, prior to development of nerve pathology and Neurofibroma formation, PLX3397 did not impair tumor initiation and increased tumor volume compared to controls. However, in mice aged 7–9 months, after tumor establishment, a subset of mice demonstrating the largest reductions in macrophages after PLX3397 exhibited cell death and tumor volume regression. Macrophages are likely to provide an initial line of defense against developing tumors. Once tumors are established, they become tumor permissive. Macrophage depletion may result in impaired tumor maintenance and represent a therapeutic strategy for Neurofibroma therapy.
-
perinatal or adult nf1 inactivation using tamoxifen inducible plpcre each cause Neurofibroma formation
Cancer Research, 2011Co-Authors: Debra A Mayes, Tilat A. Rizvi, Anat Stemmerrachamimov, Jose A Cancelas, Nathan T Kolasinski, Georgianne Ciraolo, Nancy RatnerAbstract:Plexiform Neurofibromas are peripheral nerve sheath tumors initiated by biallelic mutation of the NF1 tumor suppressor gene in the Schwann cell lineage. To understand whether Neurofibroma formation is possible after birth, we induced Nf1 loss of function with an inducible proteolipid protein Cre allele. Perinatal loss of Nf1 resulted in the development of small plexiform Neurofibromas late in life, while loss in adulthood caused large plexiform Neurofibromas and morbidity beginning 4 months after onset of Nf1 loss. A conditional EGFP reporter allele identified cells showing recombination, including peripheral ganglia satellite cells, peripheral nerve S100β+ myelinating Schwann cells, and peripheral nerve p75+ cells. Neurofibromas contained cells with Remak bundle disruption but no recombination within GFAP+ non-myelinating Schwann cells. Extramedullary lympho-hematopoietic expansion was also observed in PlpCre;Nf1fl/fl mice. These tumors contained EGFP+/Sca-1+ stromal cells among EGFP-negative lympho-hematopoietic cells indicating a non-cell autonomous effect and unveiling a role of Nf1-deleted microenvironment on lympho-hematopoietic proliferation in vivo. Together these findings define a tumor suppressor role for Nf1 in the adult and narrow the range of potential Neurofibroma-initiating cell populations.
-
nf1 mutation expands an egfr dependent peripheral nerve progenitor that confers Neurofibroma tumorigenic potential
Cell Stem Cell, 2008Co-Authors: Jon P Williams, Tilat A. Rizvi, Jianqiang Wu, Gunnar Johansson, Shyra C Miller, Hartmut Geiger, Punam Malik, Wenling Li, Yohsuke Mukouyama, Jose A CancelasAbstract:Summary Defining growth factor requirements for progenitors facilitates their characterization and amplification. We characterize a peripheral nervous system embryonic dorsal root ganglion progenitor population using in vitro clonal sphere-formation assays. Cells differentiate into glial cells, smooth muscle/fibroblast (SM/Fb)-like cells, and neurons. Genetic and pharmacologic tools revealed that sphere formation requires signaling from the EGFR tyrosine kinase. Nf1 loss of function amplifies this progenitor pool, which becomes hypersensitive to growth factors and confers tumorigenesis. DhhCre;Nf1 fl/fl mouse Neurofibromas contain a progenitor population with similar growth requirements, potential, and marker expression. In humans, NF1 mutation predisposes to benign Neurofibromas, incurable peripheral nerve tumors. Prospective identification of human EGFR + ;P75 + Neurofibroma cells enriched EGF-dependent sphere-forming cells. Neurofibroma spheres contain glial-like progenitors that differentiate into neurons and SM/Fb-like cells in vitro and form benign Neurofibroma-like lesions in nude mice. We suggest that expansion of an EGFR-expressing early glial progenitor contributes to Neurofibroma formation.