RESUMO
Angiosarcomas are aggressive vascular sarcomas that arise from endothelial cells and have an extremely poor prognosis. Because of the rarity of angiosarcomas, knowledge of molecular drivers and optimized treatment strategies is lacking, highlighting the need for in vivo models to study the disease. Previously, we generated genetically engineered mouse models of angiosarcoma driven by aP2-Cre-mediated biallelic loss of Dicer1 or conditional activation of KrasG12D with Cdkn2a loss that histologically and genetically resemble human tumors. In the present study, we found that DICER1 functions as a potent tumor suppressor and its deletion, in combination with either KRASG12D expression or Cdkn2a loss, is associated with angiosarcoma development. Independent of the genetic driver, the mTOR pathway was activated in all murine angiosarcoma models. Direct activation of the mTOR pathway by conditional deletion of Tsc1 with aP2-Cre resulted in tumors that resemble intermediate grade human kaposiform hemangioendotheliomas, indicating that mTOR activation was not sufficient to drive the malignant angiosarcoma phenotype. Genetic dissection of the spectrum of vascular tumors identified genes specifically regulated in the aggressive murine angiosarcomas that are also enriched in human angiosarcoma. The genetic dissection driving the transition across the malignant spectrum of endothelial sarcomas provides an opportunity to identify key determinants of the malignant phenotype, novel therapies for angiosarcoma, and novel in vivo models to further explore angiosarcoma pathogenesis. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Assuntos
Hemangiossarcoma , Neoplasias de Tecidos Moles , Animais , Carcinogênese , Células Endoteliais/metabolismo , Hemangiossarcoma/genética , Hemangiossarcoma/patologia , Integrases , Camundongos , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
Though outcomes for patients with recurrent/refractory malignant germ cell tumors (mGCTs) are poor, therapies targeting mTOR and EGFR inhibition have shown promise in vitro. We hypothesized that the combination of sirolimus and erlotinib will show activity in patients with recurrent/refractory mGCTs. Patients were enrolled in a prospective phase II clinical trial; central review of existing pathology specimens was performed. Of the five patients evaluated, two had their diagnoses revised to pancreatic acinar cell carcinoma and alpha-fetoprotein (AFP)-secreting gastric adenocarcinoma, respectively. Although mGCTs are common AFP-secreting neoplasms, recurrence or refractoriness to standard regimens should prompt histologic reevaluation for other diagnoses.
Assuntos
Tumor do Seio Endodérmico , Neoplasias Embrionárias de Células Germinativas , Ensaios Clínicos Fase II como Assunto , Tumor do Seio Endodérmico/diagnóstico , Tumor do Seio Endodérmico/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia , Estudos Prospectivos , alfa-FetoproteínasRESUMO
Overall survival rates for pediatric patients with high-risk or relapsed rhabdomyosarcoma (RMS) have not improved significantly since the 1980s. Recent studies have identified a number of targetable vulnerabilities in RMS, but these discoveries have infrequently translated into clinical trials. We propose streamlining the process by which agents are selected for clinical evaluation in RMS. We believe that strong consideration should be given to the development of combination therapies that add biologically targeted agents to conventional cytotoxic drugs. One example of this type of combination is the addition of the WEE1 inhibitor AZD1775 to the conventional cytotoxic chemotherapeutics, vincristine and irinotecan.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Rabdomiossarcoma , Criança , Humanos , Projetos de PesquisaRESUMO
Autosomal dominant polycystic kidney disease (ADPKD), one of the most common monogenetic disorders, is characterized by kidney failure caused by bilateral renal cyst growth. MicroRNAs (miRs) have been implicated in numerous diseases, but the role of these noncoding RNAs in ADPKD pathogenesis is still poorly defined. Here, we investigated the role of miR-21, an oncogenic miR, in kidney cyst growth. We found that transcriptional activation of miR-21 is a common feature of murine PKD. Furthermore, compared with renal tubules from kidney samples of normal controls, cysts in kidney samples from patients with ADPKD had increased levels of miR-21. cAMP signaling, a key pathogenic pathway in PKD, transactivated miR-21 promoter in kidney cells and promoted miR-21 expression in cystic kidneys of mice. Genetic deletion of miR-21 attenuated cyst burden, reduced kidney injury, and improved survival of an orthologous model of ADPKD. RNA sequencing analysis and additional in vivo assays showed that miR-21 inhibits apoptosis of cyst epithelial cells, likely through direct repression of its target gene programmed cell death 4 Thus, miR-21 functions downstream of the cAMP pathway and promotes disease progression in experimental PKD. Our results suggest that inhibiting miR-21 is a potential new therapeutic approach to slow cyst growth in PKD.
Assuntos
MicroRNAs/fisiologia , Rim Policístico Autossômico Dominante/etiologia , Rim Policístico Autossômico Dominante/patologia , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Índice de Gravidade de DoençaRESUMO
Rhabdomyosarcoma (RMS) is a pediatric embryonal solid tumor and the most common pediatric soft tissue sarcoma. The histology and transcriptome of RMS resemble skeletal muscle progenitor cells that have failed to terminally differentiate. Thus, RMS is typically thought to arise from corrupted skeletal muscle progenitor cells during development. However, RMS can occur in body regions devoid of skeletal muscle, suggesting the potential for nonmyogenic cells of origin. Here, we discuss the interplay between RMS driver mutations and cell(s) of origin with an emphasis on driving location specificity. Additionally, we discuss the mechanisms governing RMS transformation events and tumor heterogeneity through the lens of transcriptional networks and epigenetic control. Finally, we reimagine Waddington's developmental landscape to include a plane of transformation connecting distinct lineage landscapes to more accurately reflect the phenomena observed in pediatric cancers.
RESUMO
Neuroblastoma with MYCN amplification (MNA) is a high-risk disease that has a poor survival rate. Neuroblastoma displays cellular heterogeneity, including more differentiated (adrenergic) and more primitive (mesenchymal) cellular states. Here, we demonstrate that MYCN oncoprotein promotes a cellular state switch in mesenchymal cells to an adrenergic state, accompanied by induction of histone lysine demethylase 4 family members (KDM4A-C) that act in concert to control the expression of MYCN and adrenergic core regulatory circulatory (CRC) transcription factors. Pharmacologic inhibition of KDM4 blocks expression of MYCN and the adrenergic CRC transcriptome with genome-wide induction of transcriptionally repressive H3K9me3, resulting in potent anticancer activity against neuroblastomas with MNA by inducing neuroblastic differentiation and apoptosis. Furthermore, a short-term KDM4 inhibition in combination with conventional, cytotoxic chemotherapy results in complete tumor responses of xenografts with MNA. Thus, KDM4 blockade may serve as a transformative strategy to target the adrenergic CRC dependencies in MNA neuroblastomas.
Assuntos
Histona Desmetilases , Neuroblastoma , Humanos , Proteína Proto-Oncogênica N-Myc/genética , Linhagem Celular Tumoral , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Proteínas Oncogênicas/metabolismo , Histona Desmetilases com o Domínio Jumonji/genéticaRESUMO
Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma. FP-RMS histologically resembles developing muscle yet occurs throughout the body in areas devoid of skeletal muscle highlighting that FP-RMS is not derived from an exclusively myogenic cell of origin. Here we demonstrate that P3F reprograms mouse and human endothelial progenitors to FP-RMS. We show that P3F expression in aP2-Cre expressing cells reprograms endothelial progenitors to functional myogenic stem cells capable of regenerating injured muscle fibers. Further, we describe a FP-RMS mouse model driven by P3F expression and Cdkn2a loss in endothelial cells. Additionally, we show that P3F expression in TP53-null human iPSCs blocks endothelial-directed differentiation and guides cells to become myogenic cells that form FP-RMS tumors in immunocompromised mice. Together these findings demonstrate that FP-RMS can originate from aberrant development of non-myogenic cells driven by P3F.
Assuntos
Rabdomiossarcoma Alveolar , Rabdomiossarcoma , Animais , Criança , Humanos , Camundongos , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Proteína Forkhead Box O1/metabolismo , Regulação Neoplásica da Expressão Gênica , Músculo Esquelético/metabolismo , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição Box Pareados/genética , Fator de Transcrição PAX3/genética , Fator de Transcrição PAX3/metabolismo , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Rabdomiossarcoma Alveolar/genéticaRESUMO
Rearrangments in Histone-lysine-N-methyltransferase 2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis with an event-free-survival of 38%. Herein we evaluate 1116 FDA approved compounds in primary KMT2Ar infant ALL specimens and identify a sensitivity to proteasome inhibition. Upon exposure to this class of agents, cells demonstrate a depletion of histone H2B monoubiquitination (H2Bub1) and histone H3 lysine 79 dimethylation (H3K79me2) at KMT2A target genes in addition to a downregulation of the KMT2A gene expression signature, providing evidence that it targets the KMT2A transcriptional complex and alters the epigenome. A cohort of relapsed/refractory KMT2Ar patients treated with this approach on a compassionate basis had an overall response rate of 90%. In conclusion, we report on a high throughput drug screen in primary pediatric leukemia specimens whose results translate into clinically meaningful responses. This innovative treatment approach is now being evaluated in a multi-institutional upfront trial for infants with newly diagnosed ALL.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Complexo de Endopeptidases do Proteassoma , Lactente , Adulto , Humanos , Criança , Complexo de Endopeptidases do Proteassoma/genética , Lisina/genética , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , TranscriptomaRESUMO
Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic Paired Box 3-Forkhead Box O1 (PAX3-FOXO1) fusion protein, which governs a core regulatory circuitry transcription factor network. Here, we show that the histone lysine demethylase 4B (KDM4B) is a therapeutic vulnerability for PAX3-FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B substantially delayed tumor growth. Suppression of KDM4 proteins inhibited the expression of core oncogenic transcription factors and caused epigenetic alterations of PAX3-FOXO1-governed superenhancers. Combining KDM4 inhibition with cytotoxic chemotherapy led to tumor regression in preclinical PAX3-FOXO1+ RMS subcutaneous xenograft models. In summary, we identified a targetable mechanism required for maintenance of the PAX3-FOXO1-related transcription factor network, which may translate to a therapeutic approach for fusion-positive RMS.
Assuntos
Rabdomiossarcoma Alveolar , Rabdomiossarcoma , Carcinogênese/genética , Linhagem Celular Tumoral , Criança , Proteína Forkhead Box O1/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fator de Transcrição PAX3/genética , Fator de Transcrição PAX3/metabolismo , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Fatores de Transcrição Box Pareados/uso terapêutico , Rabdomiossarcoma/genética , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Alveolar/metabolismo , Rabdomiossarcoma Alveolar/patologiaRESUMO
Fusion-negative rhabdomyosarcoma (FN-RMS) is molecularly heterogeneous with few universal alterations except for Phosphatase and tensin homolog (PTEN) promoter hypermethylation. We demonstrate that losing Pten in FN-RMS engages an aberrant transcriptional program key in tumor maintenance and cell identity. These results highlight the importance between transcriptional state, cell of origin, and genetic perturbation in tumorigenesis.
RESUMO
PTEN promoter hypermethylation is nearly universal and PTEN copy number loss occurs in ~25% of fusion-negative rhabdomyosarcoma (FN-RMS). Here we show Pten deletion in a mouse model of FN-RMS results in less differentiated tumors more closely resembling human embryonal RMS. PTEN loss activated the PI3K pathway but did not increase mTOR activity. In wild-type tumors, PTEN was expressed in the nucleus suggesting loss of nuclear PTEN functions could account for these phenotypes. Pten deleted tumors had increased expression of transcription factors important in neural and skeletal muscle development including Dbx1 and Pax7. Pax7 deletion completely rescued the effects of Pten loss. Strikingly, these Pten;Pax7 deleted tumors were no longer FN-RMS but displayed smooth muscle differentiation similar to leiomyosarcoma. These data highlight how Pten loss in FN-RMS is connected to a PAX7 lineage-specific transcriptional output that creates a dependency or synthetic essentiality on the transcription factor PAX7 to maintain tumor identity.
Assuntos
Fator de Transcrição PAX7/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/patologia , Animais , Cruzamento , Diferenciação Celular , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Integrases/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Knockout , Desenvolvimento Muscular , PTEN Fosfo-Hidrolase/deficiência , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Rabdomiossarcoma/genéticaRESUMO
Rhabdomyosarcoma (RMS) histologically resembles developing skeletal muscle and is thought to solely originate from a differentiation block in muscle progenitors. We demonstrate that RMS can arise from endothelial progenitor cells following reprogramming and myogenic transdifferentiation. These results highlight how tumors with identical morphological features can arise from different cell types and offer insight into RMS formation in non-myogenic tissue.
RESUMO
Rhabdomyosarcoma is the most common soft-tissue sarcoma in childhood and histologically resembles developing skeletal muscle. Alveolar rhabdomyosarcoma (ARMS) is an aggressive subtype with a higher rate of metastasis and poorer prognosis. The majority of ARMS tumors (80%) harbor a PAX3-FOXO1 or less commonly a PAX7-FOXO1 fusion gene. The presence of either the PAX3-FOXO1 or PAX7-FOXO1 fusion gene foretells a poorer prognosis resulting in clinical re-classification as either fusion-positive (FP-RMS) or fusion-negative RMS (FN-RMS). The PAX3/7-FOXO1 fusion genes result in the production of a rogue transcription factors that drive FP-RMS pathogenesis and block myogenic differentiation. Despite knowing the molecular driver of FP-RMS, targeted therapies have yet to make an impact for patients, highlighting the need for a greater understanding of the molecular consequences of PAX3-FOXO1 and its target genes including microRNAs. Here we show FP-RMS patient-derived xenografts and cell lines display a distinct microRNA expression pattern. We utilized both loss- and gain-of function approaches in human cell lines with knockdown of PAX3-FOXO1 in FP-RMS cell lines and expression of PAX3-FOXO1 in human myoblasts and identified microRNAs both positively and negatively regulated by the PAX3-FOXO1 fusion protein. We demonstrate PAX3-FOXO1 represses miR-221/222 that functions as a tumor suppressing microRNA through the negative regulation of CCND2, CDK6, and ERBB3. In contrast, miR-486-5p is transcriptionally activated by PAX3-FOXO1 and promotes FP-RMS proliferation, invasion, and clonogenic growth. Inhibition of miR-486-5p in FP-RMS xenografts decreased tumor growth, illustrating a proof of principle for future therapeutic intervention. Therefore, PAX3-FOXO1 regulates key microRNAs that may represent novel therapeutic vulnerabilities in FP-RMS.
Assuntos
MicroRNAs/genética , Neoplasias Musculares/genética , Proteínas de Fusão Oncogênica/fisiologia , Fatores de Transcrição Box Pareados/fisiologia , Rabdomiossarcoma Alveolar/genética , Animais , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Células Cultivadas , Criança , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Camundongos , Camundongos SCID , Análise em Microsséries , Neoplasias Musculares/patologia , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição Box Pareados/genética , Rabdomiossarcoma Alveolar/patologiaRESUMO
Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma that histologically resembles embryonic skeletal muscle. RMS occurs throughout the body and an exclusively myogenic origin does not account for RMS occurring in sites devoid of skeletal muscle. We previously described an RMS model activating a conditional constitutively active Smoothened mutant (SmoM2) with aP2-Cre. Using genetic fate mapping, we show SmoM2 expression in Cre-expressing endothelial progenitors results in myogenic transdifferentiation and RMS. We show that endothelium and skeletal muscle within the head and neck arise from Kdr-expressing progenitors, and that hedgehog pathway activation results in aberrant expression of myogenic specification factors as a potential mechanism driving RMS genesis. These findings suggest that RMS can originate from aberrant development of non-myogenic cells.
Assuntos
Endotélio/metabolismo , Proteínas Hedgehog/metabolismo , Desenvolvimento Muscular/genética , Rabdomiossarcoma/metabolismo , Células-Tronco/metabolismo , Animais , Diferenciação Celular/fisiologia , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Transdução de SinaisRESUMO
Angiosarcoma is an aggressive vascular sarcoma with an extremely poor prognosis. Because of the relative rarity of this disease, its molecular drivers and optimal treatment strategies are obscure. DICER1 is an RNase III endoribonuclease central to miRNA biogenesis, and germline DICER1 mutations result in a cancer predisposition syndrome, associated with an increased risk of many tumor types. Here, we show that biallelic Dicer1 deletion with aP2-Cre drives aggressive and metastatic angiosarcoma independent of other genetically engineered oncogenes or tumor suppressor loss. Angiosarcomas in aP2-Cre;Dicer1Flox/- mice histologically and genetically resemble human angiosarcoma. miR-23 target genes, including the oncogenes Ccnd1 as well as Adam19, Plau, and Wsb1 that promote invasiveness and metastasis, were enriched in mouse and human angiosarcoma. These studies illustrate that Dicer1 can function as a traditional loss-of-function tumor suppressor gene, and they provide a fully penetrant animal model for the study of angiosarcoma development and metastasis. Cancer Res; 77(22); 6109-18. ©2017 AACR.
Assuntos
RNA Helicases DEAD-box/genética , Predisposição Genética para Doença/genética , Hemangiossarcoma/genética , Mutação , Ribonuclease III/genética , Animais , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Hemangiossarcoma/patologia , Homozigoto , Humanos , Estimativa de Kaplan-Meier , Camundongos Knockout , Camundongos Transgênicos , MicroRNAs/genéticaRESUMO
Rhabdomyosarcoma (RMS) is a mesenchymal malignancy composed of neoplastic primitive precursor cells that exhibit histological features of myogenic differentiation. Despite intensive conventional multimodal therapy, patients with high-risk RMS typically suffer from aggressive disease. The lack of directed therapies against RMS emphasizes the need to further uncover the molecular underpinnings of the disease. In this Review, we discuss the notable advances in the model systems now available to probe for new RMS-targetable pathogenetic mechanisms, and the possibilities for enhanced RMS therapeutics and improved clinical outcomes.
Assuntos
Rabdomiossarcoma/etiologia , Animais , Modelos Animais de Doenças , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/genética , Proteínas Hedgehog/fisiologia , Humanos , Mutação , Mioblastos/metabolismo , Fator de Transcrição PAX3 , Fatores de Transcrição Box Pareados/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Rabdomiossarcoma/genética , Rabdomiossarcoma/terapia , Células-Tronco/metabolismo , Proteínas ras/genéticaRESUMO
The identification and isolation of the soluble catalytic domains of adenylyl cyclase have provided investigators with useful reagents for the study of these enzymes. They have permitted detailed mechanistic investigation of the actions of forskolin, Gs alpha, and the inhibitory G protein, Gi alpha. They have served as critical reagents for the development of plausible models of the catalytic mechanism of the enzyme. They have enabled X-ray crystallographic analysis of adenylyl cyclase; this technique was not approachable with the small quantities of the membrane-bound enzyme available previously. The information obtained by using the soluble domains of adenylyl cyclase has provided templates for description of the behavior of many forms of purine nucleotide cyclases from a variety of species. We now appreciate both adenylyl cyclases and guanylyl cyclases as dimeric enzymes with a 2-fold symmetrical domain arrangement (or pseudosymmetrical in the case of heterodimerization). The active sites are located at the interface between the two domains, both of which contribute binding surfaces.
Assuntos
Adenilil Ciclases/genética , Adenilil Ciclases/isolamento & purificação , Adenilil Ciclases/análise , Adenilil Ciclases/classificação , Animais , Domínio Catalítico , Cromatografia por Troca Iônica , Colforsina/farmacologia , Citosol/enzimologia , Escherichia coli/genética , Proteínas de Ligação ao GTP/metabolismo , Expressão Gênica , Vetores Genéticos , Técnicas In Vitro , Membranas/enzimologia , Plasmídeos/genética , Estrutura Terciária de Proteína , Proteínas Recombinantes/análise , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , SolubilidadeRESUMO
Pulmonary endothelial cell apoptosis is a transient, yet defining pathogenic event integral to the onset of many pulmonary vascular diseases such as pulmonary hypertension (PH). However, there is a paucity of information concerning the molecular pathway(s) that control pulmonary arterial endothelial cell apoptosis. Here, we introduce a molecular axis that when functionally active seems to induce pulmonary arterial endothelial cell apoptosis in vitro and PH in vivo. In response to apoptotic stimuli, human pulmonary arterial endothelial cells exhibited robust induction of a programmed cell death 4 (PDCD4)/caspase-3/apoptotic pathway that was reversible by direct PDCD4 silencing. Indirectly, this pathway was also repressed by delivery of a microRNA-21 mimic. In vivo, genetic deletion of microRNA-21 in mice (miR-21(-/-) mice) resulted in functional activation of the PDCD4/caspase-3 axis in the pulmonary tissues, leading to the onset of progressive PH. Conversely, microRNA-21-overexpressing mice (CAG-microRNA-21 mice) exhibited reduced PDCD4 expression in pulmonary tissues and were partially resistant to PH in response to chronic hypoxia plus SU 5416 injury. Furthermore, direct PDCD4 knockout in mice (PDCD4(-/-) mice) potently blocked pulmonary caspase-3 activation and the development of chronic hypoxia plus SU 5416 PH, confirming its importance in disease onset. Broadly, these findings support the existence of a microRNA-21-responsive PDCD4/caspase-3 pathway in the pulmonary tissues that when active serves to promote endothelial apoptosis in vitro and PH in vivo.
Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose/fisiologia , Caspase 3/metabolismo , Células Endoteliais/metabolismo , Hipertensão Pulmonar/metabolismo , MicroRNAs/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Camundongos , MicroRNAs/genéticaRESUMO
Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and copy number variations than alveolar tumors. Mutations in the RAS/NF1 pathway are significantly associated with intermediate- and high-risk embryonal rhabdomyosarcomas (ERMS). In contrast, alveolar rhabdomyosarcomas (ARMS) have fewer genetic lesions overall and no known recurrently mutated cancer consensus genes. To identify therapeutics for ERMS, we developed and characterized orthotopic xenografts of tumors that were sequenced in our study. High-throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for ERMS.