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1.
Sci Rep ; 14(1): 20829, 2024 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-39242760

RESUMEN

This study compared the thickness of each intraretinal layer in patients with neurofibromatosis 1 (NF1) and controls to analyze the association between intraretinal layer thickness and visual function. The macular spectral-domain optical coherence tomography volumetric dataset obtained from 68 eyes (25 adult eyes, 43 pediatric eyes) with NF1 without optic glioma and 143 control eyes (100 adult eyes, 43 pediatric eyes) was used for image auto-segmentation. The intraretinal layers segmented from the volumetric data included the macular retinal nerve fiber layer (RNFL), ganglion cell-inner plexiform layer (GCIPL), inner nuclear layer, outer plexiform layer, outer nuclear layer, and photoreceptor layer. Cases and controls were compared after adjusting for age, sex, refractive error, and binocular use. The association between retinal layer thickness and visual acuity was also analyzed. The GCIPL was significantly thinner in both adult and pediatric patients with NF1 compared with healthy controls. Average RNFL and GCIPL thicknesses were associated with visual acuity in adult patients with NF1. In pediatric patients, average GCIPL thickness was associated with visual acuity. These results suggest that changes in the inner retinal layer could be a biomarker of the structural and functional status of patients with NF1.


Asunto(s)
Neurofibromatosis 1 , Retina , Tomografía de Coherencia Óptica , Agudeza Visual , Humanos , Neurofibromatosis 1/diagnóstico por imagen , Neurofibromatosis 1/patología , Femenino , Masculino , Niño , Adulto , Tomografía de Coherencia Óptica/métodos , Adolescente , Agudeza Visual/fisiología , Retina/diagnóstico por imagen , Retina/patología , Persona de Mediana Edad , Adulto Joven , Estudios de Casos y Controles , Células Ganglionares de la Retina/patología , Fibras Nerviosas/patología
2.
Skin Res Technol ; 30(9): e70020, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39225289

RESUMEN

BACKGROUND: Cutaneous neurofibromas (cNFs) are a major cause of disfigurement in patients with Neurofibromatosis Type 1 (NF1). However, clinical trials investigating cNF treatments lack standardised outcome measures to objectively evaluate changes in cNF size and appearance. 3D imaging has been proposed as an objective standardised outcome measure however various systems exist with different features that affect useability in clinical settings. The aim of this study was to compare the accuracy, precision, feasibility, reliability and accessibility of three imaging systems. MATERIALS AND METHODS: We compared the Vectra-H1, LifeViz-Micro and Cherry-Imaging systems. A total of 58 cNFs from 13 participants with NF1 were selected for imaging and analysis. The primary endpoint was accuracy as measured by comparison of measurements between imaging systems. Secondary endpoints included reliability between two operators, precision as measured with the average coefficient of variation, feasibility as determined by time to capture and analyse an image and accessibility as determined by cost. RESULTS: There was no significant difference in accuracy between the three devices for length or surface area measurements (p > 0.05), and reliability and precision were similar. Volume measurements demonstrated the most variability compared to other measurements; LifeViz-Micro demonstrated the least measurement variability for surface area and image capture and analysis were fastest with LifeViz-Micro. LifeViz-Micro was better for imaging smaller number of cNFs (1-3), Vectra-H1 better for larger areas and Cherry for uneven surfaces. CONCLUSIONS: All systems demonstrated excellent reliability but possess distinct advantages and limitations. Surface area is the most consistent and reliable parameter for measuring cNF size in clinical trials.


Asunto(s)
Imagenología Tridimensional , Neurofibromatosis 1 , Neoplasias Cutáneas , Humanos , Neurofibromatosis 1/diagnóstico por imagen , Neurofibromatosis 1/patología , Neurofibromatosis 1/complicaciones , Reproducibilidad de los Resultados , Imagenología Tridimensional/métodos , Femenino , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/patología , Masculino , Adulto , Neurofibroma/diagnóstico por imagen , Neurofibroma/patología , Adulto Joven , Diseño de Equipo , Adolescente , Sensibilidad y Especificidad , Estudios de Factibilidad , Persona de Mediana Edad , Análisis de Falla de Equipo , Dermoscopía/métodos , Dermoscopía/instrumentación
3.
Int J Mol Sci ; 25(17)2024 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-39273214

RESUMEN

Neurofibromatosis type 1 (NF1), an autosomal dominant genetic disorder, is caused by mutations in the NF1 gene, which encodes the GTPase-activating protein neurofibromin. The pathogenesis of the tumor progression of benign plexiform neurofibromas (PNs) and malignant peripheral nerve sheath tumors (MPNSTs) remain unclear. Here, we found that interferon-induced transmembrane protein 1 (IFITM1) was downregulated in MPNST tissues compared to those in PN tissues from patients with NF1. Overexpression of IFITM1 in NF1-associated MPNST cells resulted in a significant decrease in Ras activation (GTP-Ras) and downstream extracellular regulatory kinase 1/2 (ERK1/2) phosphorylation, whereas downregulation of IFITM1 via treatment with small interfering RNA in normal Schwann cells had the opposite result, indicating that expression levels of IFITM1 are closely associated with tumor progression in NF1. Treatment of MPNST cells with interferon-gamma (IFN-γ) significantly augmented the expression of IFITM1, thereby leading to a decrease in Ras and ERK1/2 activation. Despite the small number of patient samples, these findings may potentially provide a new target for chemotherapy in patients with NF1-associated MPNSTs. In xenograft mice injected with MPNST cells, IFN-γ treatment successfully suppressed tumor progression with increased IFITM1 expression and decreased Ras and ERK1/2 activation in tumor tissues. Collectively, these results suggest that IFITM1 is closely involved in MPNST pathogenesis and that IFN-γ is a good candidate for the therapeutic treatment of MPNSTs in NF1.


Asunto(s)
Antígenos de Diferenciación , Neoplasias de la Vaina del Nervio , Neurofibromatosis 1 , Humanos , Animales , Neurofibromatosis 1/metabolismo , Neurofibromatosis 1/genética , Neurofibromatosis 1/patología , Neurofibromatosis 1/complicaciones , Ratones , Neoplasias de la Vaina del Nervio/metabolismo , Neoplasias de la Vaina del Nervio/genética , Neoplasias de la Vaina del Nervio/patología , Línea Celular Tumoral , Antígenos de Diferenciación/metabolismo , Antígenos de Diferenciación/genética , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica , Masculino , Interferón gamma/metabolismo , Sistema de Señalización de MAP Quinasas , Proteínas ras/metabolismo , Proteínas ras/genética , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , Adulto
4.
PLoS One ; 19(8): e0308207, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39110684

RESUMEN

Neurofibromatosis Type 1 (NF1) is a complex genetic disorder characterized by the development of benign neurofibromas, which can cause significant morbidity in affected individuals. While the molecular mechanisms underlying NF1 pathogenesis have been extensively studied, the development of effective therapeutic strategies remains a challenge. This paper presents the development and validation of a novel biomaterial testing model to enhance our understanding of NF1 pathophysiology, disease mechanisms and evaluate potential therapeutic interventions. Our long-term goal is to develop an invitro model of NF1 to evaluate drug targets. We have developed an in vitro system to test the cellular behavior of NF1 patient derived cells on electroconductive aligned nanofibrous biomaterials with electrical stimulatory cues. We hypothesized that cells cultured on electroconductive biomaterial will undergo morphological changes and variations in cell proliferation that could be further enhanced with the combination of exogenous electrical stimulation (ES). In this study, we developed electrospun Hyaluronic Acid-Carbon Nanotube (HA-CNT) nanofiber scaffolds to mimic the axon's topographical and bioelectrical cues that influence neurofibroma growth and development. The cellular behavior was qualitatively and quantitively analyzed through immunofluorescent stains, Alamar blue assays and ELISA assays. Schwann cells from NF1 patients appear to have lost their ability to respond to electrical stimulation in the development and regeneration range, which was seen through changes in morphology, proliferation and NGF release. Without stimulation, the conductive material enhances NF1 SC behavior. Wild-type SC respond to electrical stimulation with increased cell proliferation and NGF release. Using this system, we can better understand the interaction between axons and SC that lead to tumor formation, homeostasis and regeneration.


Asunto(s)
Proliferación Celular , Estimulación Eléctrica , Ácido Hialurónico , Nanotubos de Carbono , Células de Schwann , Células de Schwann/metabolismo , Nanotubos de Carbono/química , Humanos , Ácido Hialurónico/química , Nanofibras/química , Neurofibromatosis 1/patología , Neurofibromatosis 1/metabolismo , Andamios del Tejido/química , Células Cultivadas , Materiales Biocompatibles/química
5.
Cancer Lett ; 599: 217151, 2024 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-39094827

RESUMEN

Plexiform neurofibromas (PNFs) are a prevalent and severe phenotype associated with NF1, characterized by a high teratogenic rate and potential for malignant transformation. The growth and recurrence of PNFs are attributed to aberrant proliferation and migration of Nf1-deficient Schwann cells. Protein tyrosine phosphatase receptor S (PTPRS) is believed to modulate cell migration and invasion by inhibiting the EMT process in NF1-derived malignant peripheral nerve sheath tumors. Nevertheless, the specific role of PTPRS in NF1-derived PNFs remains to be elucidated. The study utilized the GEO database and tissue microarray to illustrate a decrease in PTPRS expression in PNF tissues, linked to tumor recurrence. Furthermore, the down- and over-expression of PTPRS in Nf1-deficient Schwann cell lines resulted in the changes of cell migration and EMT processes. Additionally, RTK assay and WB showed that PTPRS knockdown can promote EGFR expression and phosphorylation. The restoration of EMT processes disrupted by alterations in PTPRS levels in Schwann cells can be achieved through EGFR knockdown and EGFR inhibitor. Moreover, high EGFR expression has been significantly correlated with poor prognosis. These findings underscore the potential role of PTPRS as a tumor suppressor in the recurrence of PNF via the regulation of EGFR-mediated EMT processes, suggesting potential targets for future clinical interventions.


Asunto(s)
Movimiento Celular , Transición Epitelial-Mesenquimal , Receptores ErbB , Neurofibroma Plexiforme , Células de Schwann , Humanos , Línea Celular Tumoral , Receptores ErbB/metabolismo , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/genética , Neurofibroma Plexiforme/patología , Neurofibroma Plexiforme/genética , Neurofibroma Plexiforme/metabolismo , Neurofibromatosis 1/genética , Neurofibromatosis 1/metabolismo , Neurofibromatosis 1/patología , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , Fosforilación , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/genética , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/metabolismo , Células de Schwann/metabolismo , Células de Schwann/patología , Transducción de Señal
7.
BMC Ophthalmol ; 24(1): 341, 2024 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-39138420

RESUMEN

BACKGROUNDS: Iris nodules are frequently noted as clinical manifestations of neurofibromatosis type 1 but the other intraocular manifestations are rare. The purpose of this study is to present a patient with a phthisic eye who underwent enucleation for a cosmetic reason after 15-year follow-up and also to review 14 patients with enucleation described in the literature. CASE PRESENTATION: A 17-year-old man with neurofibromatosis type 1 from infancy underwent the enucleation of phthisic left eye and also had the resection of eyelid subcutaneous mass lesions on the left side for a cosmetic reason. He had undergone four-time preceding surgeries for eyelid and orbital mass reduction on the left side in childhood and had developed total retinal detachment 10 years previously. Pathologically, the enucleated eye showed massive retinal gliosis positive for both S-100 and glial fibrillary acidic protein (GFAP) in the area with involvement of the detached retinal neuronal layer, together with a more fibrotic lesion along the choroid which were, in contrast, negative for both S-100 and GFAP. The choroid, ciliary body, and iris did not show apparent neurofibroma while episcleral neurofibroma was present. LITERATURE REVIEW: In review of enucleated eyes of 14 patients in the literature, buphthalmic eyes with early-onset glaucoma on the unilateral side was clinically diagnosed in 9 patients who frequently showed varying extent of hemifacial neurofibromatosis which involved the eyelid and orbit on the same side. Pathologically, neurofibromas in varying extent were found in the choroid of 12 patients. One patient showed choroidal malignant melanoma on the left side and fusiform enlargement of the optic nerve on the right side suspected of optic nerve glioma. The phthisic eye in another patient showed massive retinal gliosis similar to the present patient. CONCLUSIONS: In summary of the 15 patients with neurofibromatosis type 1, including the present patient, buphthalmic or phthisic eyes with no vision were enucleated for cosmetic reasons and showed choroidal neurofibroma in most patients and massive retinal gliosis in two patients including the present patient.


Asunto(s)
Enucleación del Ojo , Neurofibromatosis 1 , Humanos , Masculino , Adolescente , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/diagnóstico , Neurofibromatosis 1/patología , Estudios de Seguimiento
9.
J Cell Sci ; 137(15)2024 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-39016685

RESUMEN

Neurofibromatosis type 1, a genetic disorder caused by pathogenic germline variations in NF1, predisposes individuals to the development of tumors, including cutaneous and plexiform neurofibromas (CNs and PNs), optic gliomas, astrocytomas, juvenile myelomonocytic leukemia, high-grade gliomas and malignant peripheral nerve sheath tumors (MPNSTs), which are chemotherapy- and radiation-resistant sarcomas with poor survival. Loss of NF1 also occurs in sporadic tumors, such as glioblastoma (GBM), melanoma, breast, ovarian and lung cancers. We performed a high-throughput screen for compounds that were synthetic lethal with NF1 loss, which identified several leads, including the small molecule Y102. Treatment of cells with Y102 perturbed autophagy, mitophagy and lysosome positioning in NF1-deficient cells. A dual proteomics approach identified BLOC-one-related complex (BORC), which is required for lysosome positioning and trafficking, as a potential target of Y102. Knockdown of a BORC subunit using siRNA recapitulated the phenotypes observed with Y102 treatment. Our findings demonstrate that BORC might be a promising therapeutic target for NF1-deficient tumors.


Asunto(s)
Lisosomas , Neurofibromina 1 , Humanos , Lisosomas/metabolismo , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , Neurofibromatosis 1/metabolismo , Neurofibromatosis 1/genética , Neurofibromatosis 1/patología , Autofagia/efectos de los fármacos , Mutaciones Letales Sintéticas , Transporte de Proteínas/efectos de los fármacos
10.
JCI Insight ; 9(16)2024 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-38990653

RESUMEN

The neurofibromatosis type 1 (NF1) RASopathy is associated with persistent fibrotic nonunions (pseudarthrosis) in human and mouse skeletal tissue. Here, we performed spatial transcriptomics to define the molecular signatures occurring during normal endochondral healing following fracture in mice. Within the control fracture callus, we observed spatially restricted activation of morphogenetic pathways, such as TGF-ß, WNT, and BMP. To investigate the molecular mechanisms contributing to Nf1-deficient delayed fracture healing, we performed spatial transcriptomic analysis on a Postn-cre;Nf1fl/- (Nf1Postn) fracture callus. Transcriptional analyses, subsequently confirmed through phospho-SMAD1/5/8 immunohistochemistry, demonstrated a lack of BMP pathway induction in Nf1Postn mice. To gain further insight into the human condition, we performed spatial transcriptomic analysis of fracture pseudarthrosis tissue from a patient with NF1. Analyses detected increased MAPK signaling at the fibrocartilaginous-osseus junction. Similar to that in the Nf1Postn fracture, BMP pathway activation was absent within the pseudarthrosis tissue. Our results demonstrate the feasibility of delineating the molecular and tissue-specific heterogeneity inherent in complex regenerative processes, such as fracture healing, and reconstructing phase transitions representing endochondral bone formation in vivo. Furthermore, our results provide in situ molecular evidence of impaired BMP signaling underlying NF1 pseudarthrosis, potentially informing the clinical relevance of off-label BMP2 as a therapeutic intervention.


Asunto(s)
Proteínas Morfogenéticas Óseas , Curación de Fractura , Neurofibromatosis 1 , Seudoartrosis , Transducción de Señal , Transcriptoma , Animales , Seudoartrosis/metabolismo , Seudoartrosis/genética , Ratones , Humanos , Proteínas Morfogenéticas Óseas/metabolismo , Proteínas Morfogenéticas Óseas/genética , Neurofibromatosis 1/genética , Neurofibromatosis 1/metabolismo , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/patología , Curación de Fractura/genética , Fracturas Óseas/metabolismo , Fracturas Óseas/genética , Modelos Animales de Enfermedad , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , Perfilación de la Expresión Génica
11.
BMC Oral Health ; 24(1): 792, 2024 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-39004713

RESUMEN

BACKGROUND: Magnetic resonance imaging (MRI) of the brain is frequently performed on patients with neurofibromatosis type 1 (NF1), to detect and follow-up intracranial findings. In addition, NF1-related pathologies can appear in the jaws. This case study investigates if it is advantageous to assess the depicted parts of the jaws in the imaging of NF1 patients with intracranial findings, thereby detecting jaw pathologies in their initial stages. CASE PRESENTATION: We report on the 3-year management with clinical and radiological follow-ups of a central giant cell granuloma and a neurofibroma in the mandible of a patient with NF1 who underwent examinations with brain MRIs. A review of the mandible in the patient's MRIs disclosed lesions with clear differences in progression rates. CONCLUSION: NF1-related jaw pathologies may be detected in the early stages if the depicted parts of the jaws are included in the assessment of the imaging of NF1 patients with intracranial findings. This could impact the treatment of eventual pathologies before lesion progression and further damage to the vicinity.


Asunto(s)
Granuloma de Células Gigantes , Imagen por Resonancia Magnética , Neoplasias Mandibulares , Neurofibroma , Neurofibromatosis 1 , Humanos , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/diagnóstico por imagen , Neurofibromatosis 1/patología , Granuloma de Células Gigantes/diagnóstico por imagen , Granuloma de Células Gigantes/patología , Neoplasias Mandibulares/diagnóstico por imagen , Neoplasias Mandibulares/patología , Neoplasias Mandibulares/cirugía , Neurofibroma/diagnóstico por imagen , Neurofibroma/patología , Neurofibroma/cirugía , Estudios de Seguimiento , Enfermedades Mandibulares/diagnóstico por imagen , Enfermedades Mandibulares/patología , Enfermedades Mandibulares/cirugía , Femenino , Masculino
12.
J Med Genet ; 61(9): 904-907, 2024 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-38825366

RESUMEN

Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic congenital condition characterised by ocular, cutaneous and central nervous system involvement. Mosaic activating variants in FGFR1 and KRAS have been reported in several individuals with this syndrome. We report on a patient with neurofibromatosis type 1 (NF1) with a germline pathogenic variant in the NF1 gene and an ECCL phenotype, suggesting ECCL to be part of a spectrum of malformations associated with NF1 pathogenic variants. An anatomical hemispherectomy was performed for intractable epilepsy. Through genetic analysis of blood, cerebral tissue and giant cell lesions in both jaws, we identified the germline NF1 pathogenic variant in all samples and a second-hit pathogenic NF1 variant in cerebral tissue and both giant cell lesions. Both NF1 variants were located on different alleles resulting in somatic mosaicism for a biallelic NF1 inactivation originating in early embryogenesis (second-hit mosaicism or Happle type 2 mosaicism). The biallelic deficit in NF1 in the left hemicranium explains the severe localised, congenital abnormality in this patient. Identical first and second-hit variants in a giant cell lesion of both upper and lower jaws provide confirmatory evidence for an early embryonic second hit involving at least the neural crest. We suggest that the ECCL phenotype may be part of a spectrum of congenital problems associated with mosaic NF1 nullisomy originating during early embryogenesis. The biallelic NF1 inactivation during early embryogenesis mimics the severe activation of the RAS-MAPK pathway seen in ECCL caused by embryonic mosaic activating FGFR1 and KRAS variants in the cranial region. We propose that distinct mechanisms of mosaicism can cause the ECCL phenotype through convergence on the RAS-MAPK pathway.


Asunto(s)
Lipomatosis , Mosaicismo , Síndromes Neurocutáneos , Neurofibromina 1 , Fenotipo , Humanos , Lipomatosis/genética , Lipomatosis/patología , Síndromes Neurocutáneos/genética , Síndromes Neurocutáneos/patología , Neurofibromina 1/genética , Alelos , Neurofibromatosis 1/genética , Neurofibromatosis 1/patología , Femenino , Masculino , Mutación de Línea Germinal/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Oftalmopatías
13.
Sci Transl Med ; 16(753): eadj1597, 2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38924432

RESUMEN

Congenital pseudarthrosis of the tibia (CPT) is a severe pathology marked by spontaneous bone fractures that fail to heal, leading to fibrous nonunion. Half of patients with CPT are affected by the multisystemic genetic disorder neurofibromatosis type 1 (NF1) caused by mutations in the NF1 tumor suppressor gene, a negative regulator of RAS-mitogen-activated protein kinase (MAPK) signaling pathway. Here, we analyzed patients with CPT and Prss56-Nf1 knockout mice to elucidate the pathogenic mechanisms of CPT-related fibrous nonunion and explored a pharmacological approach to treat CPT. We identified NF1-deficient Schwann cells and skeletal stem/progenitor cells (SSPCs) in pathological periosteum as affected cell types driving fibrosis. Whereas NF1-deficient SSPCs adopted a fibrotic fate, NF1-deficient Schwann cells produced critical paracrine factors including transforming growth factor-ß and induced fibrotic differentiation of wild-type SSPCs. To counteract the elevated RAS-MAPK signaling in both NF1-deficient Schwann cells and SSPCs, we used MAPK kinase (MEK) and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibitors. Combined MEK-SHP2 inhibition in vivo prevented fibrous nonunion in the Prss56-Nf1 knockout mouse model, providing a promising therapeutic strategy for the treatment of fibrous nonunion in CPT.


Asunto(s)
Ratones Noqueados , Neurofibromina 1 , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Seudoartrosis , Células de Schwann , Animales , Femenino , Humanos , Masculino , Ratones , Diferenciación Celular/efectos de los fármacos , Fibrosis , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Neurofibromatosis 1/patología , Neurofibromatosis 1/metabolismo , Neurofibromatosis 1/complicaciones , Neurofibromina 1/metabolismo , Neurofibromina 1/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Seudoartrosis/patología , Seudoartrosis/metabolismo , Seudoartrosis/congénito , Células de Schwann/metabolismo , Células de Schwann/efectos de los fármacos , Células de Schwann/patología , Células Madre/metabolismo , Células Madre/efectos de los fármacos , Tibia/patología
14.
PLoS One ; 19(6): e0301040, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38900740

RESUMEN

Neurofibromatosis Type I (NF1) is a rare genetic disorder. NF1 patients frequently develop a benign tumor in peripheral nerve plexuses called plexiform neurofibroma. In the past two decades, tissue-specific Nf1 knockout mouse models were developed using commercially available tissue-specific Cre recombinase and the Nf1 flox mice to mimic neurofibroma development. However, these models develop para-spinal neurofibroma, recapitulating a rare type of neurofibroma found in NF1 patients. The NPcis mouse model developed a malignant version of neurofibroma called malignant peripheral nerve sheath tumor (MPNST) within 3 to 6 months but intriguingly without apparent benign precursor lesion. Here, we revisited the NPcis model and discovered that about 20% display clinical signs similar to Nf1 tissue-specific knockout mice models. However, a systematic histological analysis could not explain the clinical signs we observed although we noticed lesions reminiscent of a neurofibroma in a peripheral nerve, a cutaneous neurofibroma, and para-spinal neurofibroma on rare occasions in NPcis mice. We also observed that 10% of the mice developed a malignant peripheral nerve sheath tumor (MPNST) spontaneously, coinciding with their earring tag identification. Strikingly, half of the sciatic nerves from NPcis mice developed plexiform neurofibroma within 1-6 months when intentionally injured. Thus, we provided a procedure to turn the widely used NPcis sarcoma model into a model recapitulating plexiform neurofibroma.


Asunto(s)
Modelos Animales de Enfermedad , Neurofibroma Plexiforme , Animales , Neurofibroma Plexiforme/patología , Ratones , Nervio Ciático/patología , Ratones Noqueados , Neurofibromatosis 1/patología , Neurofibromatosis 1/genética , Neurofibromina 1/genética
15.
Acta Neuropathol Commun ; 12(1): 102, 2024 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-38907342

RESUMEN

Neurofibromatosis Type 1 (NF1) is caused by loss of function variants in the NF1 gene. Most patients with NF1 develop skin lesions called cutaneous neurofibromas (cNFs). Currently the only approved therapeutic for NF1 is selumetinib, a mitogen -activated protein kinase (MEK) inhibitor. The purpose of this study was to analyze the transcriptome of cNF tumors before and on selumetinib treatment to understand both tumor composition and response. We obtained biopsy sets of tumors both pre- and on- selumetinib treatment from the same individuals and were able to collect sets from four separate individuals. We sequenced mRNA from 5844 nuclei and identified 30,442 genes in the untreated group and sequenced 5701 nuclei and identified 30,127 genes in the selumetinib treated group. We identified and quantified distinct populations of cells (Schwann cells, fibroblasts, pericytes, myeloid cells, melanocytes, keratinocytes, and two populations of endothelial cells). While we anticipated that cell proportions might change with treatment, we did not identify any one cell population that changed significantly, likely due to an inherent level of variability between tumors. We also evaluated differential gene expression based on drug treatment in each cell type. Ingenuity pathway analysis (IPA) was also used to identify pathways that differ on treatment. As anticipated, we identified a significant decrease in ERK/MAPK signaling in cells including Schwann cells but most specifically in myeloid cells. Interestingly, there is a significant decrease in opioid signaling in myeloid and endothelial cells; this downward trend is also observed in Schwann cells and fibroblasts. Cell communication was assessed by RNA velocity, Scriabin, and CellChat analyses which indicated that Schwann cells and fibroblasts have dramatically altered cell states defined by specific gene expression signatures following treatment (RNA velocity). There are dramatic changes in receptor-ligand pairs following treatment (Scriabin), and robust intercellular signaling between virtually all cell types associated with extracellular matrix (ECM) pathways (Collagen, Laminin, Fibronectin, and Nectin) is downregulated after treatment. These response specific gene signatures and interaction pathways could provide clues for understanding treatment outcomes or inform future therapies.


Asunto(s)
Bencimidazoles , Matriz Extracelular , Células de Schwann , Transducción de Señal , Neoplasias Cutáneas , Humanos , Células de Schwann/efectos de los fármacos , Células de Schwann/metabolismo , Células de Schwann/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Bencimidazoles/farmacología , Matriz Extracelular/metabolismo , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/genética , Transducción de Señal/efectos de los fármacos , Neurofibroma/genética , Neurofibroma/tratamiento farmacológico , Neurofibroma/metabolismo , Neurofibroma/patología , Femenino , Masculino , RNA-Seq , Persona de Mediana Edad , Adulto , Neurofibromatosis 1/genética , Neurofibromatosis 1/tratamiento farmacológico , Neurofibromatosis 1/patología , Inhibidores de Proteínas Quinasas/farmacología , Transcriptoma/efectos de los fármacos
16.
PLoS One ; 19(6): e0304778, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38913608

RESUMEN

Neurofibromatosis type 1 (NF1) is a complex genetic disorder that affects a range of tissues including muscle and bone. Recent preclinical and clinical studies have shown that Nf1 deficiency in muscle causes metabolic changes resulting in intramyocellular lipid accumulation and muscle weakness. These can be subsequently rescued by dietary interventions aimed at modulating lipid availability and metabolism. It was speculated that the modified diet may rescue defects in cortical bone as NF1 deficiency has been reported to affect genes involved with lipid metabolism. Bone specimens were analyzed from wild type control mice as well as Nf1Prx1-/- (limb-targeted Nf1 knockout mice) fed standard chow versus a range of modified chows hypothesized to influence lipid metabolism. Mice were fed from 4 weeks to 12 weeks of age. MicroCT analysis was performed on the cortical bone to examine standard parameters (bone volume, tissue mineral density, cortical thickness) and specific porosity measures (closed pores corresponding to osteocyte lacunae, and larger open pores). Nf1Prx1-/- bones were found to have inferior bone properties to wild type bones, with a 4-fold increase in the porosity attributed to open pores. These measures were rescued by dietary interventions including a L-carnitine + medium-chain fatty acid supplemented chow previously shown to improve muscle histology function. Histological staining visualized these changes in bone porosity. These data support the concept that lipid metabolism may have a mechanistic impact on bone porosity and quality in NF1.


Asunto(s)
Modelos Animales de Enfermedad , Ratones Noqueados , Neurofibromatosis 1 , Animales , Neurofibromatosis 1/dietoterapia , Neurofibromatosis 1/patología , Neurofibromatosis 1/metabolismo , Neurofibromatosis 1/genética , Ratones , Fenotipo , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , Porosidad , Huesos/metabolismo , Huesos/patología , Metabolismo de los Lípidos , Microtomografía por Rayos X , Masculino , Densidad Ósea , Dieta
17.
Diagn Pathol ; 19(1): 78, 2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38862977

RESUMEN

BACKGROUND: Inflammatory rhabdomyoblastic tumors are relatively recently recognized soft tissue tumors with a low malignant potential. Here, we present a case of concurrent inflammatory rhabdomyoblastic tumor (IRMT), adrenal pheochromocytoma, and pulmonary hamartoma in a patient with neurofibromatosis type 1 (NF1). To our knowledge, this is the first time that this constellation of tumors has been described in the literature. CASE PRESENTATION: A female patient in her late 20s with known NF1 was diagnosed with an inflammatory rhabdomyoblastic tumor, pheochromocytoma, and pulmonary hamartoma in a short succession. IRMT was found to harbor a near-haploid genome and displayed a typical immunohistochemical profile as well as a focal aberrant p53 expression pattern. CONCLUSIONS: This case report strengthens the theory that defects in the tumor suppressor NF1 play a central role in the pathogenesis of inflammatory rhabdomyoblastic tumors and that IRMT may be part of the spectrum of neurofibromatosis type 1 related tumors.


Asunto(s)
Neoplasias de las Glándulas Suprarrenales , Hamartoma , Neurofibromatosis 1 , Feocromocitoma , Humanos , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/diagnóstico , Neurofibromatosis 1/patología , Femenino , Hamartoma/patología , Hamartoma/diagnóstico , Feocromocitoma/patología , Feocromocitoma/complicaciones , Feocromocitoma/diagnóstico , Neoplasias de las Glándulas Suprarrenales/patología , Neoplasias de las Glándulas Suprarrenales/complicaciones , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Adulto , Inmunohistoquímica , Enfermedades Pulmonares/patología , Enfermedades Pulmonares/diagnóstico , Neurofibromina 1/genética , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética
18.
Clin Neuropathol ; 43(4): 104-112, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38818730

RESUMEN

AIMS: Expression patterns of key proteins involved in RAS signaling and connected pathways were determined and correlated to possibly provide information for therapeutic application of RAS inhibitors in neurofibromatosis type 1 (NF1)-associated peripheral nerve sheath tumors (PNST). MATERIALS AND METHODS: Clinical variables (age, sex), histological parameters (cell density, mitoses), and expression of immunohistochemically evaluated ligand and receptor proteins (neuregulin 1 (NRG1), ErbB2, ErbB3), RAS pathway proteins (mTor, Rho, phosphorylated MEK), transcription factors (Pax7, Sox9), and proliferation marker Ki-67, were correlated in cutaneous (CNF, n = 136), diffuse (DNF, n = 123)/diffuse plexiform (DPNF, n = 113), and plexiform neurofibroma (PNF, n = 126), and in malignant PNST (MPNST, n = 22). RESULTS: In CNF, NRG1 correlated with Ki-67 and Pax7. Further, mTOR correlated with ErbB3, Sox9, Pax7, and Ki-67. In DNF/DPNF, expression of NRG1 correlated with pMEK and Pax7. mTOR correlated with pMEK, Sox9, and Pax7. Noteworthy, pMEK was weakly expressed in some DNF but not in DPNF. ErbB3 correlated with mTor and Ki-67. Furthermore, Rho correlated with Pax7 and Ki-67. In PNF, ErbB3 expression was associated with Sox9, mTOR, pMEK, and Pax7 as well as mTOR with Sox9 and Pax7, Rho with pMEK and Pax7, and pMEK with Pax7 and Sox9. In MPNST, only few correlations were observed, ErbB2 correlated with Ki-67, and Rho with pMEK. CONCLUSION: Signaling networks of the RAS pathway could be retraced by correlation analysis of protein expression in subgroups of NF1 associated benign PNST. In regard to treatment of PNST, MEK inhibitors, which are presently evaluated for PNF, may possibly also be effective to some extent in DNF.


Asunto(s)
Neoplasias de la Vaina del Nervio , Neurofibromatosis 1 , Transducción de Señal , Humanos , Neurofibromatosis 1/metabolismo , Neurofibromatosis 1/patología , Femenino , Masculino , Adulto , Transducción de Señal/fisiología , Persona de Mediana Edad , Adolescente , Neoplasias de la Vaina del Nervio/patología , Neoplasias de la Vaina del Nervio/metabolismo , Adulto Joven , Niño , Proteínas ras/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/análisis , Preescolar
19.
Cell Rep Methods ; 4(5): 100772, 2024 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-38744290

RESUMEN

Localized cutaneous neurofibromas (cNFs) are benign tumors that arise in the dermis of patients affected by neurofibromatosis type 1 syndrome. cNFs are benign lesions: they do not undergo malignant transformation or metastasize. Nevertheless, they can cover a significant proportion of the body, with some individuals developing hundreds to thousands of lesions. cNFs can cause pain, itching, and disfigurement resulting in substantial socio-emotional repercussions. Currently, surgery and laser desiccation are the sole treatment options but may result in scarring and potential regrowth from incomplete removal. To identify effective systemic therapies, we introduce an approach to establish and screen cNF organoids. We optimized conditions to support the ex vivo growth of genomically diverse cNFs. Patient-derived cNF organoids closely recapitulate cellular and molecular features of parental tumors as measured by immunohistopathology, methylation, RNA sequencing, and flow cytometry. Our cNF organoid platform enables rapid screening of hundreds of compounds in a patient- and tumor-specific manner.


Asunto(s)
Neurofibroma , Organoides , Neoplasias Cutáneas , Humanos , Organoides/patología , Neoplasias Cutáneas/patología , Neurofibroma/patología , Neurofibroma/cirugía , Neurofibromatosis 1/patología
20.
Am Soc Clin Oncol Educ Book ; 44(3): e432242, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38710002

RESUMEN

Most malignant peripheral nerve sheath tumors (MPNSTs) are clinically aggressive high-grade sarcomas, arising in individuals with neurofibromatosis type 1 (NF1) at a significantly elevated estimated lifetime frequency of 8%-13%. In the setting of NF1, MPNSTs arise from malignant transformation of benign plexiform neurofibroma and borderline atypical neurofibromas. Composed of neoplastic cells from the Schwannian lineage, these cancers recur in approximately 50% of individuals, and most patients die within five years of diagnosis, despite surgical resection, radiation, and chemotherapy. Treatment for metastatic disease is limited to cytotoxic chemotherapy and investigational clinical trials. In this article, we review the pathophysiology of this aggressive cancer and current approaches to surveillance and treatment.


Asunto(s)
Neoplasias de la Vaina del Nervio , Neurofibromatosis 1 , Humanos , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/terapia , Neurofibromatosis 1/patología , Neoplasias de la Vaina del Nervio/terapia , Neoplasias de la Vaina del Nervio/patología
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