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1.
Genes Dev ; 30(24): 2669-2683, 2016 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-28087712

RESUMEN

Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.


Asunto(s)
Carcinoma Ductal Pancreático/genética , Transformación Celular Neoplásica/genética , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Neoplasias Pancreáticas/genética , Transactivadores/metabolismo , Células Acinares/patología , Animales , Carcinoma Ductal Pancreático/fisiopatología , Eliminación de Gen , Proteínas de Homeodominio/genética , Humanos , Ratones , Neoplasias Pancreáticas/fisiopatología , Análisis de Matrices Tisulares , Transactivadores/genética , Células Tumorales Cultivadas
2.
Elife ; 102021 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-34009124

RESUMEN

To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA-sequencing to examine heterogeneity of murine pancreatic duct cells, pancreatobiliary cells, and intrapancreatic bile duct cells. We describe an epithelial-mesenchymal transitory axis in our three pancreatic duct subpopulations and identify osteopontin as a regulator of this fate decision as well as human duct cell dedifferentiation. Our results further identify functional heterogeneity within pancreatic duct subpopulations by elucidating a role for geminin in accumulation of DNA damage in the setting of chronic pancreatitis. Our findings implicate diverse functional roles for subpopulations of pancreatic duct cells in maintenance of duct cell identity and disease progression and establish a comprehensive road map of murine pancreatic duct cell, pancreatobiliary cell, and intrapancreatic bile duct cell homeostasis.


Asunto(s)
Perfilación de la Expresión Génica , Heterogeneidad Genética , Conductos Pancreáticos/citología , Análisis de la Célula Individual , Transcriptoma , Animales , Línea Celular , Separación Celular , Daño del ADN , Bases de Datos Genéticas , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal , Femenino , Geminina/genética , Geminina/metabolismo , Regulación del Desarrollo de la Expresión Génica , Humanos , Ratones Endogámicos C57BL , Ratones Transgénicos , Morfogénesis , Osteopontina/genética , Osteopontina/metabolismo , Conductos Pancreáticos/metabolismo , Pancreatitis Crónica/genética , Pancreatitis Crónica/metabolismo , Pancreatitis Crónica/patología , Fenotipo , RNA-Seq
4.
Nat Commun ; 9(1): 485, 2018 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-29396395

RESUMEN

Pancreatic ß cells are highly specialized to regulate systemic glucose levels by secreting insulin. In adults, increase in ß-cell mass is limited due to brakes on cell replication. In contrast, proliferation is robust in neonatal ß cells that are functionally immature as defined by a lower set point for glucose-stimulated insulin secretion. Here we show that ß-cell proliferation and immaturity are linked by tuning expression of physiologically relevant, non-oncogenic levels of c-Myc. Adult ß cells induced to replicate adopt gene expression and metabolic profiles resembling those of immature neonatal ß that proliferate readily. We directly demonstrate that priming insulin-producing cells to enter the cell cycle promotes a functionally immature phenotype. We suggest that there exists a balance between mature functionality and the ability to expand, as the phenotypic state of the ß cell reverts to a less functional one in response to proliferative cues.


Asunto(s)
Proliferación Celular/genética , Células Secretoras de Insulina/citología , Proteínas Proto-Oncogénicas c-myc/genética , Animales , Ciclo Celular , Diferenciación Celular/genética , División Celular/genética , Expresión Génica , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos/citología , Ratones , Ratones Transgénicos , Fenotipo
5.
J Clin Invest ; 128(8): 3475-3489, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-30010625

RESUMEN

Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia-derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 bound to regions of the Sox9 promoter to regulate its expression and was critical for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a dual recombinase system resulted in regression of the lesions in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.


Asunto(s)
Carcinoma Ductal Pancreático/metabolismo , Transformación Celular Neoplásica/metabolismo , ADN Helicasas/biosíntesis , Proteínas Nucleares/biosíntesis , Neoplasias Pancreáticas/metabolismo , Factor de Transcripción SOX9/metabolismo , Transducción de Señal , Factores de Transcripción/biosíntesis , Animales , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , ADN Helicasas/genética , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Transgénicos , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Elementos de Respuesta , Factor de Transcripción SOX9/genética , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias Pancreáticas
6.
Cell Metab ; 27(6): 1294-1308.e7, 2018 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-29754954

RESUMEN

To date, it remains largely unclear to what extent chromatin machinery contributes to the susceptibility and progression of complex diseases. Here, we combine deep epigenome mapping with single-cell transcriptomics to mine for evidence of chromatin dysregulation in type 2 diabetes. We find two chromatin-state signatures that track ß cell dysfunction in mice and humans: ectopic activation of bivalent Polycomb-silenced domains and loss of expression at an epigenomically unique class of lineage-defining genes. ß cell-specific Polycomb (Eed/PRC2) loss of function in mice triggers diabetes-mimicking transcriptional signatures and highly penetrant, hyperglycemia-independent dedifferentiation, indicating that PRC2 dysregulation contributes to disease. The work provides novel resources for exploring ß cell transcriptional regulation and identifies PRC2 as necessary for long-term maintenance of ß cell identity. Importantly, the data suggest a two-hit (chromatin and hyperglycemia) model for loss of ß cell identity in diabetes.


Asunto(s)
Cromatina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa , Silenciador del Gen , Células Secretoras de Insulina/metabolismo , Complejo Represivo Polycomb 2/fisiología , Animales , Diferenciación Celular/genética , Células Cultivadas , Mapeo Cromosómico , Diabetes Mellitus Tipo 2/genética , Epigenómica , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Hiperglucemia/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Complejo Represivo Polycomb 2/genética , Análisis de la Célula Individual
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