Project description:The aim of this study is to identify sites occupied by Pdx1 throughout key stages in mouse and human pancreatic development as well as during in vitro differentiation of human ES cells.
Project description:The aim of this experiment was to observe the transcriptional profile of mouse islets during development (at timepoints E18.5, P10, Adult). RNA-seq was performed on the same RNA that was used for an earlier microarray. No MARIS sorting.
Project description:Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA) making developmental regulators therapeutically attractive. Here, we demonstrate diverse functions for 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 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 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.
Project description:Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA) making developmental regulators therapeutically attractive. Here, we demonstrate diverse functions for 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 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 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.
Project description:Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA) making developmental regulators therapeutically attractive. Here, we demonstrate diverse functions for 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 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 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.
Project description:Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA) making developmental regulators therapeutically attractive. Here, we demonstrate diverse functions for 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 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 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.
Project description:Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA) making developmental regulators therapeutically attractive. Here, we demonstrate diverse functions for 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 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 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.