Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Sci Rep ; 10(1): 11133, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32636409

RESUMO

Pancreatic cancer, one of the deadliest human malignancies, has a dismal 5-year survival rate of 9%. KRAS is the most commonly mutated gene in pancreatic cancer, but clinical agents that directly target mutant KRAS are not available. Several effector pathways are activated downstream of oncogenic Kras, including MAPK signaling. MAPK signaling can be inhibited by targeting MEK1/2; unfortunately, this approach has been largely ineffective in pancreatic cancer. Here, we set out to identify mechanisms of MEK inhibitor resistance in pancreatic cancer. We optimized the culture of pancreatic tumor 3D clusters that utilized Matrigel as a basement membrane mimetic. Pancreatic tumor 3D clusters recapitulated mutant KRAS dependency and recalcitrance to MEK inhibition. Treatment of the clusters with trametinib, a MEK inhibitor, had only a modest effect on these cultures. We observed that cells adjacent to the basement membrane mimetic Matrigel survived MEK inhibition, while the cells in the interior layers underwent apoptosis. Our findings suggested that basement membrane attachment provided survival signals. We thus targeted integrin ß1, a mediator of extracellular matrix contact, and found that combined MEK and integrin ß1 inhibition bypassed trametinib resistance. Our data support exploring integrin signaling inhibition as a component of combination therapy in pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Integrina beta1/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Apoptose , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Integrina beta1/efeitos dos fármacos , Camundongos , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
2.
Elife ; 62017 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-28980940

RESUMO

Dedifferentiation of acini to duct-like cells occurs during the physiologic damage response in the pancreas, but this process can be co-opted by oncogenic Kras to drive carcinogenesis. Myeloid cells infiltrate the pancreas during the onset of pancreatic cancer, and promote carcinogenesis. Here, we show that the function of infiltrating myeloid cells is regulated by oncogenic Kras expressed in epithelial cells. In the presence of oncogenic Kras, myeloid cells promote acinar dedifferentiation and carcinogenesis. Upon inactivation of oncogenic Kras, myeloid cells promote re-differentiation of acinar cells, remodeling of the fibrotic stroma and tissue repair. Intriguingly, both aspects of myeloid cell activity depend, at least in part, on activation of EGFR/MAPK signaling, with different subsets of ligands and receptors in different target cells promoting carcinogenesis or repair, respectively. Thus, the cross-talk between epithelial cells and infiltrating myeloid cells determines the balance between tissue repair and carcinogenesis in the pancreas.


Assuntos
Células Acinares/fisiologia , Carcinogênese , Comunicação Celular , Células Epiteliais/fisiologia , Células Mieloides/fisiologia , Neoplasias Pancreáticas/fisiopatologia , Animais , Células Epiteliais/metabolismo , Receptores ErbB/metabolismo , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais
3.
Cancer Immunol Res ; 4(6): 520-30, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27068336

RESUMO

Autophagy promotes tumor progression downstream of oncogenic KRAS, yet also restrains inflammation and dysplasia through mechanisms that remain incompletely characterized. Understanding the basis of this paradox has important implications for the optimal targeting of autophagy in cancer. Using a mouse model of cerulein-induced pancreatitis, we found that loss of autophagy by deletion of Atg5 enhanced activation of the IκB kinase (IKK)-related kinase TBK1 in vivo, associated with increased neutrophil and T-cell infiltration and PD-L1 upregulation. Consistent with this observation, pharmacologic or genetic inhibition of autophagy in pancreatic ductal adenocarcinoma cells, including suppression of the autophagy receptors NDP52 or p62, prolonged TBK1 activation and increased expression of CCL5, IL6, and several other T-cell and neutrophil chemotactic cytokines in vitro Defective autophagy also promoted PD-L1 upregulation, which is particularly pronounced downstream of IFNγ signaling and involves JAK pathway activation. Treatment with the TBK1/IKKε/JAK inhibitor CYT387 (also known as momelotinib) not only inhibits autophagy, but also suppresses this feedback inflammation and reduces PD-L1 expression, limiting KRAS-driven pancreatic dysplasia. These findings could contribute to the dual role of autophagy in oncogenesis and have important consequences for its therapeutic targeting. Cancer Immunol Res; 4(6); 520-30. ©2016 AACR.


Assuntos
Autofagia/fisiologia , Pancreatite/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Doença Aguda , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Proteína 5 Relacionada à Autofagia/genética , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/biossíntese , Benzamidas/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Ceruletídeo , Quimiocina CCL5/antagonistas & inibidores , Quimiocina CCL5/metabolismo , Citocinas/metabolismo , Ativação Enzimática/genética , Deleção de Genes , Camundongos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Pancreatite/induzido quimicamente , Pancreatite/genética , Pancreatite/patologia , Pancreatite/prevenção & controle , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirimidinas/farmacologia , Transdução de Sinais/fisiologia , Células Tumorais Cultivadas
4.
Neoplasia ; 18(3): 142-51, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26992915

RESUMO

UNLABELLED: Pancreatic cancer is characterized by an extensive desmoplastic stroma, the functional relevance of which is poorly understood. Activated fibroblasts are a prevalent component of the stroma, and traditionally, these cells have been considered as a homogenous population derived from pancreatic stellate cells. In this study, we highlight a previously unappreciated heterogeneity of the fibroblast population within the stroma. In particular, a subset of stromal fibroblasts has characteristics of mesenchymal stem cells (MSCs). MSCs are present in the normal pancreas as well as in the carcinomatous pancreas (CA-MSCs). Here, we determine that CA-MSCs have increased tumor-promoting function compared with MSCs in normal pancreas. This ability to promote tumor growth is associated with CA-MSCs' unique ability to promote alternative macrophage polarization. Thus, our study identifies a previously uncharacterized cell population within the stroma and sheds light on tumor-promoting interactions between different components of the stroma. SIGNIFICANCE: Targeting the stroma is emerging as a new paradigm in pancreatic cancer; however, efforts to that effect are hampered by our limited understanding of the nature and function of stromal components. Here, we uncover previously unappreciated heterogeneity within the stroma and identify interactions among stromal components that promote tumor growth and could be targeted therapeutically.


Assuntos
Proliferação de Células/genética , Células-Tronco Mesenquimais , Neoplasias Pancreáticas/patologia , Microambiente Tumoral/genética , Diferenciação Celular/genética , Polaridade Celular/genética , Humanos , Macrófagos , Pâncreas/patologia , Neoplasias Pancreáticas/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...