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1.
Virchows Arch ; 476(1): 3-15, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31701221

RESUMO

Although traditional morphological evaluation remains the cornerstone for the diagnosis of soft tissue tumors, ancillary diagnostic modalities such as immunohistochemistry and molecular genetic analysis are of ever-increasing importance in this field. New insights into the molecular pathogenesis of soft tissue tumors, often obtained from high-throughput sequencing technologies, has enabled significant progress in the characterization and biologic stratification of mesenchymal neoplasms, expanding the spectrum of immunohistochemical tests (often aimed towards recently discovered genetic events) and molecular genetic assays (most often fluorescence in situ hybridization and reverse transcription-polymerase chain reaction). This review discusses selected novel molecular and immunohistochemical assays with diagnostic applicability in mesenchymal neoplasms, with emphasis on diagnosis, refinement of tumor classification, and treatment stratification.


Assuntos
Neoplasias de Tecidos Moles/diagnóstico , DNA Helicases/análise , Fusão Gênica , Humanos , Imuno-Histoquímica , Proteínas Nucleares/análise , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-fos/genética , Proteína EWS de Ligação a RNA/genética , Receptor trkA/genética , Proteínas Repressoras/genética , Proteína SMARCB1/análise , Neoplasias de Tecidos Moles/química , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Fatores de Transcrição/análise
2.
Nat Commun ; 10(1): 4343, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554817

RESUMO

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.


Assuntos
Neoplasias Encefálicas/genética , Metilação de DNA , Epigenômica/métodos , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Receptores Proteína Tirosina Quinases/genética , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/metabolismo , Feminino , Glioma/classificação , Glioma/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptor trkA/genética , Receptor trkA/metabolismo , Análise de Sobrevida , Sequenciamento Completo do Exoma/métodos
3.
Nat Med ; 25(9): 1422-1427, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31406350

RESUMO

TRK fusions are found in a variety of cancer types, lead to oncogenic addiction, and strongly predict tumor-agnostic efficacy of TRK inhibition1-8. With the recent approval of the first selective TRK inhibitor, larotrectinib, for patients with any TRK-fusion-positive adult or pediatric solid tumor, to identify mechanisms of treatment failure after initial response has become of immediate therapeutic relevance. So far, the only known resistance mechanism is the acquisition of on-target TRK kinase domain mutations, which interfere with drug binding and can potentially be addressable through second-generation TRK inhibitors9-11. Here, we report off-target resistance in patients treated with TRK inhibitors and in patient-derived models, mediated by genomic alterations that converge to activate the mitogen-activated protein kinase (MAPK) pathway. MAPK pathway-directed targeted therapy, administered alone or in combination with TRK inhibition, re-established disease control. Experimental modeling further suggests that upfront dual inhibition of TRK and MEK may delay time to progression in cancer types prone to the genomic acquisition of MAPK pathway-activating alterations. Collectively, these data suggest that a subset of patients will develop off-target mechanisms of resistance to TRK inhibition with potential implications for clinical management and future clinical trial design.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Receptor trkA/genética , Adolescente , Adulto , Animais , Benzamidas/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Ácidos Nucleicos Livres/efeitos dos fármacos , Ácidos Nucleicos Livres/genética , Criança , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Xenoenxertos , Humanos , Imidazóis/administração & dosagem , Indazóis/administração & dosagem , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Terapia de Alvo Molecular , Neoplasias/genética , Neoplasias/patologia , Oximas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Pirimidinas/administração & dosagem , Pirimidinonas/administração & dosagem , Adulto Jovem
4.
Nat Commun ; 10(1): 3718, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31420543

RESUMO

High throughput omics approaches provide an unprecedented opportunity for dissecting molecular mechanisms in cancer biology. Here we present deep profiling of whole proteome, phosphoproteome and transcriptome in two high-grade glioma (HGG) mouse models driven by mutated RTK oncogenes, PDGFRA and NTRK1, analyzing 13,860 proteins and 30,431 phosphosites by mass spectrometry. Systems biology approaches identify numerous master regulators, including 41 kinases and 23 transcription factors. Pathway activity computation and mouse survival indicate the NTRK1 mutation induces a higher activation of AKT downstream targets including MYC and JUN, drives a positive feedback loop to up-regulate multiple other RTKs, and confers higher oncogenic potency than the PDGFRA mutation. A mini-gRNA library CRISPR-Cas9 validation screening shows 56% of tested master regulators are important for the viability of NTRK-driven HGG cells, including TFs (Myc and Jun) and metabolic kinases (AMPKa1 and AMPKa2), confirming the validity of the multiomics integrative approaches, and providing novel tumor vulnerabilities.


Assuntos
Neoplasias Encefálicas/genética , Perfilação da Expressão Gênica , Glioma/genética , Proteômica , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Modelos Animais de Doenças , Retroalimentação Fisiológica , Glioma/metabolismo , Camundongos , Mutação , Proteína Oncogênica p65(gag-jun)/metabolismo , Fosfopeptídeos/metabolismo , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor trkA/genética , Transdução de Sinais , Biologia de Sistemas , Regulação para Cima
5.
BMC Cancer ; 19(1): 592, 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31208361

RESUMO

BACKGROUND: Pulmonary sarcomatoid carcinoma (SC) consists of both carcinomatous and sarcomatous tumors with high degree of malignancy, rapid progression, and poor prognosis. However, little is known regarding how pulmonary SC develops and progresses. CASE PRESENTATION: A 66-year-old male was initially diagnosed with stage IIIa lung cancer containing both adenocarcinoma (ADC) and SC. Adjuvant chemotherapy was administrated post-surgery, however, recurrence with SC only soon followed. Mutation profiling of the patient's microdissected ADC and SC components of the primary lesion and recurrent tumor was performed by targeted next-generation sequencing (NGS) of 416 cancer-relevant genes. Our data showed that primary SC/ADC and the recurrent SC shared multiple gene mutations including EGFR, NF1, TP53, CDKN2B, and SMARCA4, while both primary and recurrent SCs had a unique TP53 exon 4 splicing mutation frequently observed in sarcoma. Interestingly, a novel PHF20-NTRK1 fusion was acquired in the recurrent SC, which may be a potential driver for SC recurrence. CONCLUSIONS: The molecular genetic characteristics of tumor tissues at different stages reveals a linear tumor evolution model in this case, and support that the primary SC derived from the original lung ADC during the evolution of the tumor. We also identified a novel PHF20-NTRK1 fusion, which may contribute to the disease recurrence, and that can be potentially targeted with NTRK1 inhibitors for treatment.


Assuntos
Adenocarcinoma de Pulmão/complicações , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Carcinossarcoma/etiologia , Fusão Gênica , Neoplasias Pulmonares/complicações , Doenças Raras/etiologia , Receptor trkA/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/radioterapia , Adenocarcinoma de Pulmão/cirurgia , Idoso , Carcinogênese , Carcinossarcoma/tratamento farmacológico , Carcinossarcoma/radioterapia , Carcinossarcoma/cirurgia , Quimioterapia Adjuvante , Éxons/genética , Evolução Fatal , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Masculino , Recidiva Local de Neoplasia , Doenças Raras/tratamento farmacológico , Doenças Raras/radioterapia , Doenças Raras/cirurgia
6.
J Clin Pathol ; 72(7): 460-467, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31072837

RESUMO

The neurotrophic tyrosine receptor kinase (NTRK) gene family encodes three tropomyosin receptor kinases (TRKA, TRKB, TRKC) that contribute to central and peripheral nervous system development and function. NTRK gene fusions are oncogenic drivers of various adult and paediatric tumours. Several methods have been used to detect NTRK gene fusions including immunohistochemistry, fluorescence in situ hybridisation, reverse transcriptase polymerase chain reaction, and DNA- or RNA-based next-generation sequencing. For patients with TRK fusion cancer, TRK inhibition is an important therapeutic target. Following the FDA approval of the selective TRK inhibitor, larotrectinib, as well as the ongoing development of multi-kinase inhibitors with activity in TRK fusion cancer, testing for NTRK gene fusions should become part of the standard diagnostic process. In this review we discuss the biology of NTRK gene fusions, and we present a testing algorithm to aid detection of these gene fusions in clinical practice and guide treatment decisions.


Assuntos
Neoplasias/genética , Fatores de Crescimento Neural/genética , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Receptores Proteína Tirosina Quinases/genética , Algoritmos , Humanos , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Fatores de Crescimento Neural/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptor trkA/antagonistas & inibidores , Receptor trkA/genética , Receptor trkB/antagonistas & inibidores , Receptor trkB/genética , Receptor trkC/antagonistas & inibidores , Receptor trkC/genética
7.
Oncology ; 97(1): 26-37, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31071716

RESUMO

OBJECTIVE: Normally, activation of tropomyosin-related kinase (TRK) receptors by neurotrophins (NTs) stimulates intracellular pathways involved in cell survival and proliferation. Dysregulation of NT/TRK signaling may affect neoplasm prognosis. Data on NT and TRK expression in melanomas are limited, and it is unclear whether NT/TRK signaling pathways are involved in the origin and progression of this neoplasm. METHODS: We examined whether NT/TRK expression differs across different cutaneous melanoma grades and subtypes, and whether it is associated with melanoma prognosis and survival. A cross-sectional study was performed in which the expression of TrkA, TrkB, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) was analyzed by immunohistochemistry of 154 melanoma samples. We investigated NT/TRK expression associations with prognostic factors for melanoma, relapse-free survival (RFS), and overall survival (OS). RESULTS: Of the 154 melanoma samples, 77 (55.4%) were TrkA immunopositive, 81 (58.3%) were TrkB immunopositive, 113 (81.3%) were BDNF immunopositive, and 104 (75.4%) were NGF immunopositive. We found NT/TRK expression associated strongly with several clinical prognostic factors, including the tumor-node-metastasis stage (p < 0.001), histological subtype (p < 0.001), and Clark level (p < 0.05), as well as with a worse OS (p < 0.05 for all, except TrkB) and RFS (p < 0.05 for all). CONCLUSIONS: Our results show strong associations of NT/TRK expression with melanoma stage progression and a poor prognosis.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Melanoma/genética , Glicoproteínas de Membrana/genética , Fatores de Crescimento Neural/genética , Receptor trkA/genética , Receptor trkB/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/imunologia , Melanoma/patologia , Glicoproteínas de Membrana/imunologia , Pessoa de Meia-Idade , Fator de Crescimento Neural/genética , Fatores de Crescimento Neural/imunologia , Prognóstico , Receptor trkA/imunologia , Receptor trkB/imunologia , Transdução de Sinais , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Adulto Jovem
8.
Cell Physiol Biochem ; 52(6): 1361-1380, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31075188

RESUMO

BACKGROUND/AIMS: Human Dental Pulp Stem Cells (hDPSCs) are one of the most promising types of cells to regenerate nerve tissues. Standard DMEM+10% fetal bovine serum (FBS) culture medium allows a fast expansion of hDPSC as a surface-adherent cell monolayer. However, the use of FBS also compromises the clinical use of these protocols, and its longterm presence favors hDPSCs differentiation toward mesenchymal cell-derived lineages, at the expense of a reduced capability to generate neural cells. The objective of this work was to characterize the role of neurotrophin signaling on hDPSCs using a serum-free culture protocol, and to assess the neurogenic and gliogenic capacity of hDPSCs for future nerve tissue bioengineering and regeneration. METHODS: We compared the different expression of neurotrophin receptors by RT-PCR, Q-PCR, and IF of hDPSCs cultured with different growth media in the presence or absence of serum. Moreover, we assessed the response of hDPSCs to stimulation of neurotransmitter receptors by live cell calcium imaging under these different media. Finally, we compared the osteogenic potential of hDPSCs by Alizarin red staining, and the differentiation to gliogenic/neurogenic fates by immunostaining for Schwann lineage and neuronal lineage markers. We tested a commercial serum-free medium designed for the growth of mesenchymal stem cells: StemPro MSCTM (STP). RESULTS: hDPSCs cultured in STP generated small non-adherent floating dentospheres that showed very low proliferation rates, in contrast to standard FBS-containing medium. We found that hDPSCs grown in STP conditions overexpressed neurotrophin receptor genes NTRK2 (TrkB) and NTRK3 (TrkC). Interestingly, the stimulation of these receptors by adding their respective ligands BDNF and NT-3 to STP medium enhanced the neural crest (NC) progenitor features of cultured hDPSCs. We observed a 10 to 100-fold increase of migratory NC cell markers HNK1 and P75NTR, and a significant overexpression of pluripotency core factors SOX2, OCT4 and NANOG. Moreover, hDPSCs cultured in BDNF/NT-3 supplemented STP showed a largely increased potential to differentiate towards neuronal and Schwann glial lineage cells, assessed by positive immunostaining for DCX, NeuN and S100ß, p75NTR markers, respectively. CONCLUSION: Our results demonstrate that the use of BDNF and NT-3 combined with STP induced the partial reprogramming of ectomesenchymal hDPSCs to generate early NC progenitor cells, which are far more competent for neuronal and glial differentiation than hDPSCs grown in the presence of FBS.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/farmacologia , Reprogramação Celular/efeitos dos fármacos , Meios de Cultura Livres de Soro/farmacologia , Fatores de Crescimento Neural/farmacologia , Adolescente , Adulto , Antígenos CD57/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Polpa Dentária/citologia , Humanos , Canais Iônicos/genética , Canais Iônicos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Crista Neural/citologia , Neurogênese/efeitos dos fármacos , Receptor trkA/genética , Receptor trkA/metabolismo , Receptores de Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Adulto Jovem
9.
Indian J Pharmacol ; 51(1): 31-39, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031465

RESUMO

CONTEXT: Homology modeling plays role in determining the therapeutic targets dreadful for condition such as neurodegenerative diseases (NDD), which pose challenge in achieving the effective managements. The structures of the serotonin transporter (SERT), aquaporin (AQP), and tropomyosin receptor kinase (TrkA) which are implicated in NDD pathology are still unknown for Lumbricus terrestris, but the three-dimensional (3D) structure of the human counterpart for modeling. AIM: This study aims to generate and evaluate the 3D structure of TrkA, SERT, and AQP proteins and their interaction with the ligands, namely Asiaticoside-D (AD) and levodopa (L-DOPA) the anti-NDD agents. SUBJECTS AND METHODS: Homology modeling for SERT, AQP, and TrkA proteins of Lumbricus terrestris using SWISS-MODEL Server and the modeled structure was validated using Rampage Server. Wet-lab analysis of their correspondent m-RNA levels was also done to validate the in silico data. RESULTS: It was found that TrkA had moderately high homology (67%) to human while SERT and AQP could exhibit 58% and 42%, respectively. The reliability of the model was assessed by Ramachandran plot analysis. Interactions of AD with the SERT, AQP-4, and TrkA showed the binding energies as -9.93, 8.88, and -7.58 of Kcal/mol, respectively, while for L-DOPA did show -3.93, -5.13, and -6.0 Kcal/mol, respectively. The levels of SERT, TrkA, and AQP-4 were significantly reduced (P < 0.001) on ROT induced when compared to those of control worms. On ROT + AD supplementation group (III), m-RNA levels were significantly increased (P < 0.05) when compared to those of ROT induced worms (group II). CONCLUSION: Our pioneering docking data propose the possible of target which is proved useful for therapeutic investigations against the unconquered better of NDD.


Assuntos
Aquaporinas/metabolismo , Levodopa/farmacologia , Modelos Moleculares , Fármacos Neuroprotetores/farmacologia , Receptor trkA/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Triterpenos/farmacologia , Animais , Aquaporinas/genética , Gânglios dos Invertebrados/efeitos dos fármacos , Gânglios dos Invertebrados/lesões , Gânglios dos Invertebrados/metabolismo , Oligoquetos , Receptor trkA/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
10.
Brain Tumor Pathol ; 36(3): 121-128, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31011918

RESUMO

Here, we report a highly unusual case of high-grade glioneuronal tumor with a neurotrophic tropomyosin receptor kinase (NTRK) fusion gene. A 13-year-old girl presented with headache and vomiting and MRI detected two cystic lesions bilaterally in the frontal areas with surrounding edema. The left larger tumor was removed by left frontal craniotomy. The tumor was diagnosed as a high-grade glioneuronal tumor, unclassified. Methylation profiling classified it as a diffuse leptomeningeal glioneuronal tumor (DLGNT) with low confidence. This tumor showed genotypes frequently found in DLGNT such as 1p/19q codeletion without IDH mutation and, however, did not have the typical DLGNT clinical and histological features. RNA sequencing identified an ARHGEF2 (encoding Rho/Rac guanine nucleotide exchange factor 2)-NTRK1 fusion gene. The presence of recurrent NTRK fusion in glioneuronal tumors has an important implication in the clinical decision making and opens up a possibility of novel targeted therapy.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioma/genética , Glioma/patologia , Proteínas de Fusão Oncogênica/genética , Receptor trkA/genética , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Adolescente , Deleção Cromossômica , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 19 , Feminino , Fusão Gênica , Humanos , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Mutação , Oligodendroglioma/genética , Oligodendroglioma/patologia , Proteínas de Fusão Oncogênica/metabolismo , Receptor trkA/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo
11.
Nat Commun ; 10(1): 1745, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988299

RESUMO

Early childhood is a critical period for development, and early life stress may increase the risk of gastrointestinal diseases including irritable bowel syndrome (IBS). In rodents, neonatal maternal separation (NMS) induces bowel dysfunctions that resemble IBS. However, the underlying mechanisms remain unclear. Here we show that NMS induces expansion of intestinal stem cells (ISCs) and their differentiation toward secretory lineages including enterochromaffin (EC) and Paneth cells, leading to EC hyperplasia, increased serotonin production, and visceral hyperalgesia. This is reversed by inhibition of nerve growth factor (NGF)-mediated tropomyosin receptor kinase A (TrkA) signalling, and treatment with NGF recapitulates the intestinal phenotype of NMS mice in vivo and in mouse intestinal organoids in vitro. Mechanistically, NGF transactivates Wnt/ß-catenin signalling. NGF and serotonin are positively correlated in the sera of diarrhea-predominant IBS patients. Together, our findings provide mechanistic insights into early life stress-induced intestinal changes that may translate into treatments for gastrointestinal diseases.


Assuntos
Gastroenteropatias/etiologia , Estresse Fisiológico , Animais , Células Enterocromafins/patologia , Humanos , Hiperplasia/patologia , Privação Materna , Camundongos , Fator de Crescimento Neural/metabolismo , Fator de Crescimento Neural/fisiologia , Receptor trkA/genética , Receptor trkA/metabolismo , Receptor trkA/fisiologia , Transdução de Sinais , Via de Sinalização Wnt
13.
Am J Surg Pathol ; 43(6): 737-746, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30844834

RESUMO

Activating NTRK1 fusions have been described as oncogenic events across the spectrum of Spitz tumors. Herein we report a series of 38 Spitz tumors with NTRK1 fusion. These Spitz tumors have distinctive histopathologic features characterized by filigree-like rete ridges which are elongated, thin and branched, dermal melanocytes arranged in a rosette-like configuration, and marked diminishment of melanocyte size with descent into the dermis. These features are distinct from those of other genetically defined subtypes of Spitz tumors and can aid in microscopic diagnosis and help prioritize in case selection for molecular testing in the rare patients that need targeted therapy.


Assuntos
Biomarcadores Tumorais/genética , Fusão Gênica , Melanócitos/patologia , Melanoma/genética , Melanoma/patologia , Nevo de Células Epitelioides e Fusiformes/genética , Nevo de Células Epitelioides e Fusiformes/patologia , Receptor trkA/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , França , Predisposição Genética para Doença , Humanos , Masculino , Melanoma/terapia , Pessoa de Meia-Idade , Nevo de Células Epitelioides e Fusiformes/terapia , Fenótipo , Prognóstico , Neoplasias Cutâneas/terapia , Estados Unidos , Adulto Jovem
14.
Nat Commun ; 10(1): 1129, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850602

RESUMO

Optical control over the activity of receptor tyrosine kinases (RTKs) provides an efficient way to reversibly and non-invasively map their functions. We combined catalytic domains of Trk (tropomyosin receptor kinase) family of RTKs, naturally activated by neurotrophins, with photosensory core module of DrBphP bacterial phytochrome to develop opto-kinases, termed Dr-TrkA and Dr-TrkB, reversibly switchable on and off with near-infrared and far-red light. We validated Dr-Trk ability to reversibly light-control several RTK pathways, calcium level, and demonstrated that their activation triggers canonical Trk signaling. Dr-TrkA induced apoptosis in neuroblastoma and glioblastoma, but not in other cell types. Absence of spectral crosstalk between Dr-Trks and blue-light-activatable LOV-domain-based translocation system enabled intracellular targeting of Dr-TrkA independently of its activation, additionally modulating Trk signaling. Dr-Trks have several superior characteristics that make them the opto-kinases of choice for regulation of RTK signaling: high activation range, fast and reversible photoswitching, and multiplexing with visible-light-controllable optogenetic tools.


Assuntos
Fatores de Crescimento Neural/genética , Neuroglia/efeitos da radiação , Neurônios/efeitos da radiação , Fitocromo/genética , Receptor trkA/genética , Receptor trkB/genética , Animais , Apoptose/genética , Apoptose/efeitos da radiação , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Linhagem Celular Tumoral , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Células Epiteliais/efeitos da radiação , Regulação da Expressão Gênica , Células HeLa , Humanos , Raios Infravermelhos , Transdução de Sinal Luminoso , Camundongos , Fatores de Crescimento Neural/metabolismo , Neuroglia/citologia , Neuroglia/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Optogenética/métodos , Fitocromo/metabolismo , Engenharia de Proteínas , Receptor trkA/metabolismo , Receptor trkB/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo
15.
Acta Derm Venereol ; 99(6): 579-586, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30809683

RESUMO

Prurigo nodularis is a highly pruritic and hyperplastic chronic dermatosis with unknown pathogenesis. Many pruritogenic mediators, including nerve growth factor, interleukin (IL)-31, thymic stromal lymphopoietin, and endothelin-1, are implicated in chronic itch and inflammation. This study investigated the mRNA levels and immunoreactivity of the nerve growth factor, IL-31, thymic stromal lymphopoietin, and endothelin axes in both lesional and perilesional skin in prurigo nodularis by using quantitative real-time PCR and immunohistochemistry studies. The nerve growth factor high-affinity receptor tyrosine kinase receptor A was upregulated while the low affinity receptor p75 neurotrophin receptor was downregulated in prurigo nodularis lesions. Downregulated expression of IL-31/IL-31 receptor A and endothelin-3/endothelin receptor B and upregulation of thymic stromal lymphopoietin receptor were found in prurigo nodularis lesions. Aberrant expression of nerve growth factor, IL-31, thymic stromal lymphopoietin and endothelin axes was found in prurigo nodularis lesions, especially in the epidermis, indicating the importance of keratinocytes in prurigo nodularis pathogenesis.


Assuntos
Epiderme/metabolismo , Queratinócitos/metabolismo , Prurigo/genética , Prurigo/metabolismo , Adulto , Citocinas/genética , Citocinas/metabolismo , Regulação para Baixo , Endotelina-3/genética , Endotelina-3/metabolismo , Feminino , Expressão Gênica , Humanos , Hipersensibilidade/complicações , Hipersensibilidade/genética , Hipersensibilidade/metabolismo , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Prurigo/complicações , RNA Mensageiro/metabolismo , Receptor de Endotelina B/genética , Receptor de Endotelina B/metabolismo , Receptor trkA/genética , Receptor trkA/metabolismo , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Receptores de Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/metabolismo , Regulação para Cima
16.
J Neurol ; 266(5): 1107-1112, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30767057

RESUMO

Collagen XIII is a non-fibrillar transmembrane collagen which has been long recognized for its critical role in synaptic maturation of the neuromuscular junction. More recently, biallelic COL13A1 loss-of-function mutations were identified in three patients with congenital myasthenic syndrome (CMS), a rare inherited condition with defective neuromuscular transmission, causing abnormal fatigability and fluctuating muscle weakness and often successfully treated with acetylcholinesterase inhibitors. Here we report six additional CMS patients from three unrelated families with previously unreported homozygous COL13A1 loss-of-function mutations (p.Tyr216*, p.Glu543fs and p.Thr629fs). The phenotype of our cases was similar to the previously reported patients including respiratory distress and severe dysphagia at birth that often resolved or improved in the first days or weeks of life. All individuals had prominent eyelid ptosis with only minor ophthalmoparesis as well as generalized muscle weakness, predominantly affecting facial, bulbar, respiratory and axial muscles. Response to acetylcholinesterase inhibitor treatment was generally negative while salbutamol proved beneficial. Our data further support the causality of COL13A1 variants for CMS and suggest that this type of CMS might be clinically homogenous and requires alternative pharmacological therapy.


Assuntos
Colágeno Tipo XIII/genética , Mutação/genética , Síndromes Miastênicas Congênitas/genética , Criança , Consanguinidade , Análise Mutacional de DNA , Saúde da Família , Feminino , Humanos , Masculino , Síndromes Miastênicas Congênitas/patologia , Síndromes Miastênicas Congênitas/fisiopatologia , Receptor trkA/genética , Adulto Jovem
17.
Cancer Lett ; 449: 196-206, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30771434

RESUMO

ProNGF expression has been linked to several types of cancers including breast cancer, and we have previously shown that proNGF stimulates breast cancer invasion in an autocrine manner through membrane receptors sortilin and TrkA. However, little is known regarding TrkA-associated protein partners upon proNGF stimulation. By proteomic analysis and proximity ligation assays, we found that proNGF binding to sortilin induced sequential formation of the functional sortilin/TrkA/EphA2 complex, leading to TrkA-phosphorylation dependent Akt activation and EphA2-dependent Src activation. EphA2 inhibition using siRNA approach abolished proNGF-stimulated clonogenic growth of breast cancer cell lines. Combinatorial targeting of TrkA and EphA2 dramatically reduced colony formation in vitro, primary tumor growth and metastatic dissemination towards the brain in vivo. Finally, proximity ligation assay in breast tumor samples revealed that increased TrkA/EphA2 proximity ligation assay signals were correlated with a decrease of overall survival in patients. All together, these data point out the importance of TrkA/EphA2 functional association in proNGF-induced tumor promoting effects, and provide a rationale to target proNGF/TrkA/EphA2 axis by alternative methods other than the simple use of tyrosine kinase inhibitors in breast cancer.


Assuntos
Neoplasias da Mama/enzimologia , Proliferação de Células , Efrina-A2/metabolismo , Fator de Crescimento Neural/metabolismo , Precursores de Proteínas/metabolismo , Receptor trkA/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/prevenção & controle , Neoplasias Encefálicas/secundário , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Efrina-A2/genética , Feminino , Humanos , Células MCF-7 , Camundongos SCID , Fosforilação , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Terapêutica com RNAi , Receptor trkA/antagonistas & inibidores , Receptor trkA/genética , Transdução de Sinais , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/metabolismo
18.
J Clin Pathol ; 72(3): 187-190, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30636697

RESUMO

The neurotrophic tropomyosin or tyrosine receptor kinase (NTRK) genes (1-3) are proto-oncogenes that when activated are encountered in a wide array of tumours. The recent advent of very specific and selective inhibitors of their gene fusions makes the NRTK gene fusions actionable. NRTK gene fusions are very characteristic of specific tumours: salivary mammary analogue secretory carcinoma, breast secretory carcinoma, infantile fibrosarcoma and congenital mesoblastic nephroma. Over 90% of these tumours bear NTRK gene fusions. While next-generation sequencing is the current platform of choice for the detection of NTRK fusions, immunohistochemistry also shows great promise. Immunohistochemical localisation of the fusion protein to the nucleus, cytoplasm, nuclear membrane and cell membrane is indicative of specific gene fusions involving the NTRK genes.


Assuntos
Receptor trkA/genética , Receptor trkB/genética , Receptor trkC/genética , Animais , Humanos
19.
Genes Chromosomes Cancer ; 58(8): 558-566, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30664823

RESUMO

Papillary thyroid carcinoma (PTC) is most common among all thyroid cancers. Multiple genomic alterations occur in PTC, and gene rearrangements are one of them. Here we screened 14 tumors for novel fusion transcripts by RNA-Seq. Two samples harboring RET/PTC1 and RET/PTC3 rearrangements were positive controls whereas the remaining ones were negative regarding the common PTC alterations. We used Sanger sequencing to validate potential fusions. We detected 2 novel potentially oncogenic transcript fusions: TG-FGFR1 and TRIM33-NTRK1. We detected 4 novel fusion transcripts of unknown significance accompanying the TRIM33-NTRK1 fusion: ZSWIM5-TP53BP2, TAF4B-WDR1, ABI2-MTA3, and ARID1B-PSMA1. Apart from confirming the presence of RET/PTC1 and RET/PTC3 in positive control samples, we also detected known oncogenic fusion transcripts in remaining samples: TFG-NTRK1, ETV6-NTRK3, MKRN1-BRAF, EML4-ALK, and novel isoform of CCDC6-RET.


Assuntos
Biomarcadores Tumorais , Proteínas de Fusão Oncogênica/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor trkA/genética , Câncer Papilífero da Tireoide/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Feminino , Humanos , Masculino , Análise de Sequência de DNA , Câncer Papilífero da Tireoide/diagnóstico , Carga Tumoral , Adulto Jovem
20.
Mod Pathol ; 32(1): 147-153, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30171197

RESUMO

Targeted inhibitors of neurotropic tyrosine kinases are highly effective in selected patients with gene fusions involving NTRK1, NTRK2, or NTRK3. These fusions are consistently detected in rare cancer types (e.g., secretory breast carcinoma and congenital infantile fibrosarcoma), but the occurrence of NTRK fusions in common cancers and their relationship to other therapy biomarkers are largely unexplored. Tissue samples from 11,502 patients were analyzed for 53 gene fusions and sequencing of 592 genes, along with an immunohistochemical evaluation of TrkA/B/C and PD-L1. Thirty-one cases (0.27% of the entire cohort) had NTRK fusions. The most common fusions were ETV6:NTRK3 (n = 10) and TPM3:NTRK1 (n = 6). Gliomas had the highest number of NTRK fusions (14/982, 1.4%), most commonly involving NTRK2 (n = 9). Seventeen non-glioma cases with NTRK fusions included carcinomas of the lungs, thyroid, breast, cervix, colon, nasal cavity, cancer of unknown primary and soft tissue sarcomas. Strong and uniform Trk expression detected with a pan-Trk immunohistochemistry characterized 7/8 NTRK1 fusion cases and 8/9 NTRK2 fusion cases, while NTRK3 fused cases were positive in 6/11 (55%) of cases. 29% of NTRK fusion cases had no other pathogenic genomic alteration. PD-L1 expression was observed in 23% of NTRK fused cases while high tumor DNA microsatellite instability was detected in two cases. We confirm the rarity of NTRK genes fusions outside the brain malignancies. NTRK inhibitors alone or combined with immune checkpoint inhibitors may be a therapeutic option for a substantial proportion of these patients. Strategies for detection of the NTRK fusion-driven cancers may include immunohistochemistry, but gene fusion detection remains the most reliable tool.


Assuntos
Receptor com Domínio Discoidina 2/genética , Glicoproteínas de Membrana/genética , Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , Receptor trkA/genética , Receptor trkB/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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