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1.
Cancer Discov ; 9(8): 1102-1123, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31197017

RESUMEN

Cancer-associated fibroblasts (CAF) are major players in the progression and drug resistance of pancreatic ductal adenocarcinoma (PDAC). CAFs constitute a diverse cell population consisting of several recently described subtypes, although the extent of CAF heterogeneity has remained undefined. Here we use single-cell RNA sequencing to thoroughly characterize the neoplastic and tumor microenvironment content of human and mouse PDAC tumors. We corroborate the presence of myofibroblastic CAFs and inflammatory CAFs and define their unique gene signatures in vivo. Moreover, we describe a new population of CAFs that express MHC class II and CD74, but do not express classic costimulatory molecules. We term this cell population "antigen-presenting CAFs" and find that they activate CD4+ T cells in an antigen-specific fashion in a model system, confirming their putative immune-modulatory capacity. Our cross-species analysis paves the way for investigating distinct functions of CAF subtypes in PDAC immunity and progression. SIGNIFICANCE: Appreciating the full spectrum of fibroblast heterogeneity in pancreatic ductal adenocarcinoma is crucial to developing therapies that specifically target tumor-promoting CAFs. This work identifies MHC class II-expressing CAFs with a capacity to present antigens to CD4+ T cells, and potentially to modulate the immune response in pancreatic tumors.See related commentary by Belle and DeNardo, p. 1001.This article is highlighted in the In This Issue feature, p. 983.


Asunto(s)
Presentación de Antígeno/inmunología , Fibroblastos Asociados al Cáncer/inmunología , Fibroblastos Asociados al Cáncer/metabolismo , Carcinoma Ductal Pancreático/etiología , Carcinoma Ductal Pancreático/metabolismo , Neoplasias Pancreáticas/etiología , Neoplasias Pancreáticas/metabolismo , Animales , Fibroblastos Asociados al Cáncer/patología , Carcinoma Ductal Pancreático/patología , Técnica del Anticuerpo Fluorescente , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Ratones , Modelos Biológicos , Neoplasias Pancreáticas/patología , Análisis de la Célula Individual , Microambiente Tumoral/inmunología
2.
Science ; 364(6446): 1156-1162, 2019 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-31221853

RESUMEN

Glycosylation alterations are indicative of tissue inflammation and neoplasia, but whether these alterations contribute to disease pathogenesis is largely unknown. To study the role of glycan changes in pancreatic disease, we inducibly expressed human fucosyltransferase 3 and ß1,3-galactosyltransferase 5 in mice, reconstituting the glycan sialyl-Lewisa, also known as carbohydrate antigen 19-9 (CA19-9). Notably, CA19-9 expression in mice resulted in rapid and severe pancreatitis with hyperactivation of epidermal growth factor receptor (EGFR) signaling. Mechanistically, CA19-9 modification of the matricellular protein fibulin-3 increased its interaction with EGFR, and blockade of fibulin-3, EGFR ligands, or CA19-9 prevented EGFR hyperactivation in organoids. CA19-9-mediated pancreatitis was reversible and could be suppressed with CA19-9 antibodies. CA19-9 also cooperated with the KrasG12D oncogene to produce aggressive pancreatic cancer. These findings implicate CA19-9 in the etiology of pancreatitis and pancreatic cancer and nominate CA19-9 as a therapeutic target.


Asunto(s)
Antígeno CA-19-9/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Receptores ErbB/metabolismo , Neoplasias Pancreáticas/metabolismo , Pancreatitis/metabolismo , Enfermedad Aguda , Animales , Antígeno CA-19-9/inmunología , Carcinogénesis/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Enfermedad Crónica , Proteínas de la Matriz Extracelular/metabolismo , Fucosiltransferasas/genética , Fucosiltransferasas/metabolismo , Galactosiltransferasas/genética , Galactosiltransferasas/metabolismo , Glicosilación , Humanos , Ratones , Terapia Molecular Dirigida/métodos , Neoplasias Pancreáticas/patología , Pancreatitis/patología
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