RESUMO
Pancreatic ductal adenocarcinoma (PDAC) has single-digit 5-year survival rates at <7%. There is a dire need to improve pre-malignant detection methods and identify new therapeutic targets for abrogating PDAC progression. To this end, we mined our previously published pseudopodium-enriched (PDE) protein/phosphoprotein datasets to identify novel PDAC-specific biomarkers and/or therapeutic targets. We discovered that integrin alpha 1 (ITGA1) is frequently upregulated in pancreatic cancers and associated precursor lesions. Expression of ITGA1-specific collagens within the pancreatic cancer microenvironment significantly correlates with indicators of poor patient prognosis, and depleting ITGA1 from PDAC cells revealed that it is required for collagen-induced tumorigenic potential. Notably, collagen/ITGA1 signaling promotes the survival of ALDH1-positive stem-like cells and cooperates with TGFß to drive gemcitabine resistance. Finally, we report that ITGA1 is required for TGFß/collagen-induced EMT and metastasis. Our data suggest that ITGA1 is a new diagnostic biomarker and target that can be leveraged to improve patient outcomes.
Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Cadeias alfa de Integrinas/genética , Neoplasias Pancreáticas/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Família Aldeído Desidrogenase 1 , Animais , Antimetabólitos Antineoplásicos/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide/irrigação sanguínea , Membrana Corioalantoide/efeitos dos fármacos , Colágeno/genética , Colágeno/metabolismo , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Transição Epitelial-Mesenquimal , Humanos , Cadeias alfa de Integrinas/antagonistas & inibidores , Cadeias alfa de Integrinas/metabolismo , Isoenzimas/genética , Isoenzimas/metabolismo , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Retinal Desidrogenase/genética , Retinal Desidrogenase/metabolismo , Transdução de Sinais , Análise Serial de Tecidos , Fator de Crescimento Transformador beta/farmacologia , Microambiente Tumoral/genética , GencitabinaRESUMO
ABSTRACT: Native pastures are of great importance for cattle and sheep nutrition in the Pampa biome. However, due to its low productivity, the Italian ryegrass introduction and the nitrogen (N) fertilization are alternatives proposed to intensify livestock production in a sustainable manner. The objective of this study was to evaluate the effects of long-term N application on soil health indicators in a native pasture with Italian ryegrass introduction in southern Brazil. The experiment consists of a secondary native pasture under continuous grazing and constant herbage allowance. In 1996 experimental area was broadcast limed and the experiment was initiated, testing three N topdressing rates (0, 100 and 200kg N ha-1 year-1). In 2010 soil of experimental and reference area of non grazed native grassland was sampled in the soil layers of 0-20 and 20-40cm. Total, particulate and mineral associated carbon (C) and N stocks were evaluated. Soil microbiological attributes were evaluated in 0-5 and 5-10cm soil layers. The long-term N fertilization in soils with native pasture and Italian ryegrass introduction did not affect total C and N stocks. However, increases in N particulate fraction were seen with 100kg ha-1 year-1 of N rate of fertilization. Furthermore, the increase in N rates increased N microbial biomass and respiration.
RESUMO: A pastagem nativa é uma importante fonte de forragem para produção de bovinos e ovinos no bioma Pampa. A introdução do azevém e a fertilização nitrogenada são alternativas que visam intensificar a exploração pecuária de forma mais sustentável, podendo causar alterações em vários atributos do solo. Este trabalho teve por objetivo avaliar os efeitos de longo prazo de fertilização nitrogenada sobre atributos indicadores da saúde do solo em pastagem nativa com introdução de azevém anual. O experimento consistiu de uma sucessão secundária da pastagem natural submetida ao pastejo contínuo por bovinos e ovinos, com oferta de forragem constante. Em 1996, anteriormente ao inicio do experimento, a área experimental foi calcareada para correção da acidez do solo. O experimento foi então iniciado, sendo constituído da aplicação de três doses de N em cobertura, correspondendo a 0, 100 e 200kg ha-1 ano-1 de N. Em 2010, amostras de solo foram coletadas nas camadas de 0-20 e 20-40cm para análise de C e N total, particulado e associado aos minerais, além de uma área de referência (campo nativo sem pastejo). Análises microbiológicas foram conduzidas nas camadas de 0-5 e 5-10cm. A adubação nitrogenada de longo prazo em solos de campo nativo com introdução de azevém não altera os estoques totais de C e N, mas aumenta a fração particulada de N na dose de 100kg ha-1 ano-1. Em relação à atividade microbiana, o aumento na dose do fertilizante aumenta a respiração dos microrganismos, assim como o N da sua biomassa.
RESUMO
Transforming Growth Factor ß (TGFß) has dual functions as both a tumor suppressor and a promoter of cancer progression within the tumor microenvironment, but the molecular mechanisms by which TGFß signaling switches between these outcomes and the contexts in which this switch occurs remain to be fully elucidated. We previously identified PEAK1 as a new non-receptor tyrosine kinase that associates with the cytoskeleton, and facilitates signaling of HER2/Src complexes. We also showed PEAK1 functions downstream of KRas to promote tumor growth, metastasis and therapy resistance using preclinical in vivo models of human tumor progression. In the current study, we analyzed PEAK1 expression in human breast cancer samples and found PEAK1 levels correlate with mesenchymal gene expression, poor cellular differentiation and disease relapse. At the cellular level, we also observed that PEAK1 expression was highest in mesenchymal breast cancer cells, correlated with migration potential and increased in response to TGFß-induced epithelial-mesenchymal transition (EMT). Thus, we sought to evaluate the role of PEAK1 in the switching of TGFß from a tumor suppressing to tumor promoting factor. Notably, we discovered that high PEAK1 expression causes TGFß to lose its anti-proliferative effects, and potentiates TGFß-induced proliferation, EMT, cell migration and tumor metastasis in a fibronectin-dependent fashion. In the presence of fibronectin, PEAK1 caused a switching of TGFß signaling from its canonical Smad2/3 pathway to non-canonical Src and MAPK signaling. This report is the first to provide evidence that PEAK1 mediates signaling cross talk between TGFß receptors and integrin/Src/MAPK pathways and that PEAK1 is an important molecular regulator of TGFß-induced tumor progression and metastasis in breast cancer. Finally, PEAK1 overexpression/upregulation cooperates with TGFß to reduce breast cancer sensitivity to Src kinase inhibition. These findings provide a rational basis to develop therapeutic agents to target PEAK1 expression/function or upstream/downstream pathways to abrogate breast cancer progression.
