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1.
Int J Mol Sci ; 19(9)2018 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-30235830

RESUMO

Hedgehog signaling pathway is physiologically activated during embryogenesis, especially in lung development. It is also reactivated in many solid tumors. In lung cancer, Hedgehog pathway is closely associated with cancer stem cells (CSCs). Recent works have shown that CSCs produced a full-length Sonic Hedgehog (Shh) protein, with paracrine activity and induction of tumor development. Hedgehog pathway is also involved in tumor drug resistance in lung cancer, as cytotoxic chemotherapy, radiotherapy, and targeted therapies. This review proposes to describe the activation mechanisms of Hedgehog pathway in lung cancer, the clinical implications for overcoming drug resistance, and the perspectives for further research.


Assuntos
Carcinogênese/metabolismo , Proteínas Hedgehog/metabolismo , Neoplasias Pulmonares/metabolismo , Transdução de Sinais , Animais , Carcinogênese/genética , Resistencia a Medicamentos Antineoplásicos , Proteínas Hedgehog/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , Tolerância a Radiação
2.
Development ; 141(19): 3782-92, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25209249

RESUMO

Arteriovenous malformations (AVMs) are tortuous vessels characterized by arteriovenous (AV) shunts, which displace capillaries and shunt blood directly from artery to vein. Notch signaling regulates embryonic AV specification by promoting arterial, as opposed to venous, endothelial cell (EC) fate. To understand the essential role of endothelial Notch signaling in postnatal AV organization, we used inducible Cre-loxP recombination to delete Rbpj, a mediator of canonical Notch signaling, from postnatal ECs in mice. Deletion of endothelial Rbpj from birth resulted in features of AVMs by P14, including abnormal AV shunting and tortuous vessels in the brain, intestine and heart. We further analyzed brain AVMs, as they pose particular health risks. Consistent with AVM pathology, we found cerebral hemorrhage, hypoxia and necrosis, and neurological deficits. AV shunts originated from capillaries (and possibly venules), with the earliest detectable morphological abnormalities in AV connections by P8. Prior to AV shunt formation, alterations in EC gene expression were detected, including decreased Efnb2 and increased Pai1, which encodes a downstream effector of TGFß signaling. After AV shunts had formed, whole-mount immunostaining showed decreased Efnb2 and increased Ephb4 expression within AV shunts, suggesting that ECs were reprogrammed from arterial to venous identity. Deletion of Rbpj from adult ECs led to tortuosities in gastrointestinal, uterine and skin vascular beds, but had mild effects in the brain. Our results demonstrate a temporal requirement for Rbpj in postnatal ECs to maintain proper artery, capillary and vein organization and to prevent abnormal AV shunting and AVM pathogenesis.


Assuntos
Malformações Arteriovenosas/genética , Malformações Arteriovenosas/patologia , Endotélio Vascular/metabolismo , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/deficiência , Receptores Notch/metabolismo , Transdução de Sinais/fisiologia , Animais , Deleção de Genes , Perfilação da Expressão Gênica , Processamento de Imagem Assistida por Computador , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Camundongos , Microscopia de Fluorescência , Reação em Cadeia da Polimerase em Tempo Real , Receptor EphB4/metabolismo
3.
J Clin Invest ; 134(18)2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38980870

RESUMO

Reciprocal interactions between alveolar fibroblasts and epithelial cells are crucial for lung homeostasis, injury repair, and fibrogenesis, but underlying mechanisms remain unclear. To investigate, we administered the fibroblast-selective TGF-ß1 signaling inhibitor epigallocatechin gallate (EGCG) to interstitial lung disease (ILD) patients undergoing diagnostic lung biopsy and conducted single-cell RNA-Seq on spare tissue. Biopsies from untreated patients showed higher fibroblast TGF-ß1 signaling compared with nondisease donor or end-stage ILD tissues. In vivo, EGCG downregulated TGF-ß1 signaling and several proinflammatory and stress pathways in biopsy samples. Notably, EGCG reduced fibroblast secreted frizzled-related protein 2 (sFRP2), an unrecognized TGF-ß1 fibroblast target gene induced near type II alveolar epithelial cells (AEC2s) in situ. Using AEC2-fibroblast coculture organoids and precision-cut lung slices (PCLSs) from nondiseased donors, we found TGF-ß1 signaling promotes a spread AEC2 KRT17+ basaloid state, whereupon sFRP2 then activates a mature cytokeratin 5+ (Krt5+) basal cell program. Wnt-receptor Frizzled 5 (Fzd5) expression and downstream calcineurin signaling were required for sFRP2-induced nuclear NFATc3 accumulation and KRT5 expression. These findings highlight stage-specific TGF-ß1 signaling in ILD and the therapeutic potential of EGCG in reducing idiopathic pulmonary fibrosis-related (IPF-related) transcriptional changes and identify TGF-ß1/noncanonical Wnt pathway crosstalk via sFRP2 as a mechanism for dysfunctional epithelial signaling in IPF/ILD.


Assuntos
Fibroblastos , Fibrose Pulmonar Idiopática , Metaplasia , Fator de Crescimento Transformador beta1 , Via de Sinalização Wnt , Humanos , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genética , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , Metaplasia/metabolismo , Metaplasia/patologia , Masculino , Feminino , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Animais , Camundongos , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Pessoa de Meia-Idade
4.
Stem Cell Reports ; 18(3): 636-653, 2023 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-36827975

RESUMO

Ancestral SARS coronavirus-2 (SARS-CoV-2) and variants of concern (VOC) caused a global pandemic with a spectrum of disease severity. The mechanistic explaining variations related to airway epithelium are relatively understudied. Here, we biobanked airway organoids (AO) by preserving stem cell function. We optimized viral infection with H1N1/PR8 and comprehensively characterized epithelial responses to SARS-CoV-2 infection in phenotypically stable AO from 20 different subjects. We discovered Tetraspanin-8 (TSPAN8) as a facilitator of SARS-CoV-2 infection. TSPAN8 facilitates SARS-CoV-2 infection rates independently of ACE2-Spike interaction. In head-to-head comparisons with Ancestral SARS-CoV-2, Delta and Omicron VOC displayed lower overall infection rates of AO but triggered changes in epithelial response. All variants shared highest tropism for ciliated and goblet cells. TSPAN8-blocking antibodies diminish SARS-CoV-2 infection and may spur novel avenues for COVID-19 therapy.


Assuntos
COVID-19 , Vírus da Influenza A Subtipo H1N1 , Humanos , SARS-CoV-2 , Organoides , Tetraspaninas/genética
5.
Sci Rep ; 11(1): 23690, 2021 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-34880292

RESUMO

Although surgery for early-stage lung cancer offers the best chance of cure, recurrence still occurs between 30 and 50% of the time. Why patients frequently recur after complete resection of early-stage lung cancer remains unclear. Using a large cohort of stage I lung adenocarcinoma patients, distinct genetic, genomic, epigenetic, and immunologic profiles of recurrent tumors were analyzed using a novel recurrence classifier. To characterize the tumor immune microenvironment of recurrent stage I tumors, unique tumor-infiltrating immune population markers were identified using single cell RNA-seq on a separate cohort of patients undergoing stage I lung adenocarcinoma resection and applied to a large study cohort using digital cytometry. Recurrent stage I lung adenocarcinomas demonstrated higher mutation and lower methylation burden than non-recurrent tumors, as well as widespread activation of known cancer and cell cycle pathways. Simultaneously, recurrent tumors displayed downregulation of immune response pathways including antigen presentation and Th1/Th2 activation. Recurrent tumors were depleted in adaptive immune populations, and depletion of adaptive immune populations and low cytolytic activity were prognostic of stage I recurrence. Genomic instability and impaired adaptive immune responses are key features of stage I lung adenocarcinoma immunosurveillance escape and recurrence after surgery.


Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Biomarcadores Tumorais , Adenocarcinoma de Pulmão/diagnóstico , Biologia Computacional/métodos , Suscetibilidade a Doenças , Epigênese Genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Variação Genética , Humanos , Masculino , Mutação , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Microambiente Tumoral/genética
6.
bioRxiv ; 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34100012

RESUMO

SARS coronavirus-2 (SARS-CoV-2) is causing a global pandemic with large variation in COVID-19 disease spectrum. SARS-CoV-2 infection requires host receptor ACE2 on lung epithelium, but epithelial underpinnings of variation are largely unknown. We capitalized on comprehensive organoid assays to report remarkable variation in SARS-CoV-2 infection rates of lung organoids from different subjects. Tropism is highest for TUBA- and MUC5AC-positive organoid cells, but levels of TUBA-, MUC5A-, or ACE2- positive cells do not predict infection rate. We identify surface molecule Tetraspanin 8 (TSPAN8) as novel mediator of SARS-CoV-2 infection, which is not downregulated by this specific virus. TSPAN8 levels, prior to infection, strongly correlate with infection rate and TSPAN8-blocking antibodies diminish SARS-CoV-2 infection. We propose TSPAN8 as novel functional biomarker and potential therapeutic target for COVID-19.

7.
J Mol Med (Berl) ; 85(11): 1281-9, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17593335

RESUMO

Dishevelled is a key component of the Wnt signaling and planar polarity pathways. We discovered that in selective cell types, it potently activates the transcriptional activity of the tumor suppressor p53. This action, however, is not dependent on the downstream of either the Wnt or the planar polarity pathways. Dishevelled signals to the first 50 amino acids of p53, which is the transactivation domain. The level of phosphorylation on several serine residues within that region of p53 increases in response to disheveled activation, partially contributing to p53 activation. The MAP kinase pathway and E1B55k may also be involved in this dishevelled-p53 connection. Our data provide evidence that there is a novel signaling pathway from Dishevelled to p53.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fosfoproteínas/metabolismo , Transdução de Sinais , Ativação Transcricional/genética , Proteína Supressora de Tumor p53/genética , Proteínas E1B de Adenovirus/metabolismo , Animais , Linhagem Celular , Dano ao DNA , Proteínas Desgrenhadas , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Ratos , Transdução de Sinais/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos , Proteína Supressora de Tumor p53/química , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
8.
Ther Clin Risk Manag ; 12: 807-16, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27307741

RESUMO

Compared to adenocarcinoma, fewer effective treatment options are available for advanced or metastatic squamous cell carcinoma (SCC) of the lung. Afatinib is an orally administered, irreversible EGFR antagonist. As a second-generation tyrosine kinase inhibitor, it has been applied in the treatment of patients with EGFR-mutant non-small-cell lung cancer. Recently, several clinical trials have shown that afatinib leads to a significant improvement in progression-free survival and overall survival of patients with SCC. Moving forward, afatinib should be one of the options among tyrosine kinase inhibitors, monoclonal antibodies, and cytotoxicity chemotherapy drugs for SCC.

9.
Mol Cell Biol ; 30(9): 2264-79, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20160012

RESUMO

The neurofibromatosis type 1 (NF1) gene encodes the GTPase-activating protein (GAP) neurofibromin, which negatively regulates Ras activity. The yeast Saccharomyces cerevisiae has two neurofibromin homologs, Ira1 and Ira2. To understand how these proteins are regulated, we utilized an unbiased proteomics approach to identify Ira2 and neurofibromin binding partners. We demonstrate that the Gpb1/Krh2 protein binds and negatively regulates Ira2 by promoting its ubiquitin-dependent proteolysis. We extended our findings to show that in mammalian cells, the ETEA/UBXD8 protein directly interacts with and negatively regulates neurofibromin. ETEA contains both UBA and UBX domains. Overexpression of ETEA downregulates neurofibromin in human cells. Purified ETEA, but not a mutant of ETEA that lacks the UBX domain, ubiquitinates the neurofibromin GAP-related domain in vitro. Silencing of ETEA expression increases neurofibromin levels and downregulates Ras activity. These findings provide evidence for conserved ubiquitination pathways regulating the RasGAP proteins Ira2 (in yeast) and neurofibromin (in humans).


Assuntos
Proteínas Sanguíneas/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Neurofibromina 1/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Sanguíneas/química , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Glucose/farmacologia , Humanos , Espectrometria de Massas , Proteínas de Membrana , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Proteínas de Saccharomyces cerevisiae/química , Ubiquitinação/efeitos dos fármacos
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