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The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma.

Krah NM, De La O JP, Swift GH, Hoang CQ, Willet SG, Chen Pan F, Cash GM, Bronner MP, Wright CV, MacDonald RJ, Murtaugh LC - Elife (2015)

Bottom Line: Loss of Ptf1a alone is sufficient to induce acinar-to-ductal metaplasia, potentiate inflammation, and induce a KRAS-permissive, PDAC-like gene expression profile.As a result, Ptf1a-deficient acinar cells are dramatically sensitized to KRAS transformation, and reduced Ptf1a greatly accelerates development of invasive PDAC.Together, these data indicate that cell differentiation regulators constitute a new tumor suppressive mechanism in the pancreas.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, University of Utah, Salt Lake City, United States.

ABSTRACT
Understanding the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) may provide therapeutic strategies for this deadly disease. Recently, we and others made the surprising finding that PDAC and its preinvasive precursors, pancreatic intraepithelial neoplasia (PanIN), arise via reprogramming of mature acinar cells. We therefore hypothesized that the master regulator of acinar differentiation, PTF1A, could play a central role in suppressing PDAC initiation. In this study, we demonstrate that PTF1A expression is lost in both mouse and human PanINs, and that this downregulation is functionally imperative in mice for acinar reprogramming by oncogenic KRAS. Loss of Ptf1a alone is sufficient to induce acinar-to-ductal metaplasia, potentiate inflammation, and induce a KRAS-permissive, PDAC-like gene expression profile. As a result, Ptf1a-deficient acinar cells are dramatically sensitized to KRAS transformation, and reduced Ptf1a greatly accelerates development of invasive PDAC. Together, these data indicate that cell differentiation regulators constitute a new tumor suppressive mechanism in the pancreas.

No MeSH data available.


Related in: MedlinePlus

Ptf1a suppresses fibroinflammatory pathways and oncogenic KRAS associated gene signatures.(A) Volcano plot showing differentially expressed genes (false discovery rate [FDR] <0.05; gray) in Ptf1a cKO pancreata, relative to control. Individual genes are labeled and highlighted in black. Genes belonging to signatures characteristic of RAS dependency, classical and exocrine-like pancreatic ductal adenocarcinoma (PDAC) are highlighted in pink, green, and blue, respectively. Table below indicates p-values from binomial test for enrichment of gene signatures within up- or down-regulated genes. (B) Gene Set Enrichment Analysis (GSEA) enrichment plots of differentially expressed genes between Ptf1a cKO and control indicating positive enrichment of RAS dependency and classical PDAC signatures and negative enrichment of exocrine-like PDAC signature genes. (C, D) Ingenuity Pathway Analysis (IPA, Qiagen Redwood City, www.qiagen.com/ingenuity) was used to identify differentially expressed pathways and upstream regulators in Ptf1a cKO pancreata. (C) Heat map of pathways that are significantly increased and decreased upon Ptf1a deletion. (D) Heat map of upstream pathways and regulators predicted to drive the observed changes in gene expression. Color scale is indicative of the -log p-value (significance). All analyses are based on a ±2.0-fold expression threshold. Full details of the data set and analyses can be found in the supplementary data files.DOI:http://dx.doi.org/10.7554/eLife.07125.016
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fig5: Ptf1a suppresses fibroinflammatory pathways and oncogenic KRAS associated gene signatures.(A) Volcano plot showing differentially expressed genes (false discovery rate [FDR] <0.05; gray) in Ptf1a cKO pancreata, relative to control. Individual genes are labeled and highlighted in black. Genes belonging to signatures characteristic of RAS dependency, classical and exocrine-like pancreatic ductal adenocarcinoma (PDAC) are highlighted in pink, green, and blue, respectively. Table below indicates p-values from binomial test for enrichment of gene signatures within up- or down-regulated genes. (B) Gene Set Enrichment Analysis (GSEA) enrichment plots of differentially expressed genes between Ptf1a cKO and control indicating positive enrichment of RAS dependency and classical PDAC signatures and negative enrichment of exocrine-like PDAC signature genes. (C, D) Ingenuity Pathway Analysis (IPA, Qiagen Redwood City, www.qiagen.com/ingenuity) was used to identify differentially expressed pathways and upstream regulators in Ptf1a cKO pancreata. (C) Heat map of pathways that are significantly increased and decreased upon Ptf1a deletion. (D) Heat map of upstream pathways and regulators predicted to drive the observed changes in gene expression. Color scale is indicative of the -log p-value (significance). All analyses are based on a ±2.0-fold expression threshold. Full details of the data set and analyses can be found in the supplementary data files.DOI:http://dx.doi.org/10.7554/eLife.07125.016

Mentions: In order to investigate further the mechanism of ADM after loss of Ptf1a, we performed RNA-seq on whole pancreata from three control and three Ptf1a cKO mice, each of which received three doses of TM (0.25 mg/g) to induce maximal recombination 2 weeks prior to RNA extraction. Initial analysis of RNA-seq data sets by edgeR (Robinson et al., 2010), setting a false discovery rate (FDR) threshold of 0.05, identified significant changes in expression of over 3000 total genes (Figure 5A). Consistent with our immunostaining (Figure 4), among the most significantly downregulated mRNAs were Ptf1a (18.4-fold) and Cpa1 (5.45-fold), while Sox9 was significantly upregulated (4.61-fold) in Ptf1a cKO pancreata (Figure 5A). Additional downregulated mRNAs included a wide variety of digestive enzymes and other secreted proteins characteristic of the exocrine acinar phenotype, consistent with the long-standing hypothesis that they are directly regulated by PTF1A (Rose et al., 2001; MacDonald et al., in preparation).10.7554/eLife.07125.016Figure 5.Ptf1a suppresses fibroinflammatory pathways and oncogenic KRAS associated gene signatures.


The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma.

Krah NM, De La O JP, Swift GH, Hoang CQ, Willet SG, Chen Pan F, Cash GM, Bronner MP, Wright CV, MacDonald RJ, Murtaugh LC - Elife (2015)

Ptf1a suppresses fibroinflammatory pathways and oncogenic KRAS associated gene signatures.(A) Volcano plot showing differentially expressed genes (false discovery rate [FDR] <0.05; gray) in Ptf1a cKO pancreata, relative to control. Individual genes are labeled and highlighted in black. Genes belonging to signatures characteristic of RAS dependency, classical and exocrine-like pancreatic ductal adenocarcinoma (PDAC) are highlighted in pink, green, and blue, respectively. Table below indicates p-values from binomial test for enrichment of gene signatures within up- or down-regulated genes. (B) Gene Set Enrichment Analysis (GSEA) enrichment plots of differentially expressed genes between Ptf1a cKO and control indicating positive enrichment of RAS dependency and classical PDAC signatures and negative enrichment of exocrine-like PDAC signature genes. (C, D) Ingenuity Pathway Analysis (IPA, Qiagen Redwood City, www.qiagen.com/ingenuity) was used to identify differentially expressed pathways and upstream regulators in Ptf1a cKO pancreata. (C) Heat map of pathways that are significantly increased and decreased upon Ptf1a deletion. (D) Heat map of upstream pathways and regulators predicted to drive the observed changes in gene expression. Color scale is indicative of the -log p-value (significance). All analyses are based on a ±2.0-fold expression threshold. Full details of the data set and analyses can be found in the supplementary data files.DOI:http://dx.doi.org/10.7554/eLife.07125.016
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fig5: Ptf1a suppresses fibroinflammatory pathways and oncogenic KRAS associated gene signatures.(A) Volcano plot showing differentially expressed genes (false discovery rate [FDR] <0.05; gray) in Ptf1a cKO pancreata, relative to control. Individual genes are labeled and highlighted in black. Genes belonging to signatures characteristic of RAS dependency, classical and exocrine-like pancreatic ductal adenocarcinoma (PDAC) are highlighted in pink, green, and blue, respectively. Table below indicates p-values from binomial test for enrichment of gene signatures within up- or down-regulated genes. (B) Gene Set Enrichment Analysis (GSEA) enrichment plots of differentially expressed genes between Ptf1a cKO and control indicating positive enrichment of RAS dependency and classical PDAC signatures and negative enrichment of exocrine-like PDAC signature genes. (C, D) Ingenuity Pathway Analysis (IPA, Qiagen Redwood City, www.qiagen.com/ingenuity) was used to identify differentially expressed pathways and upstream regulators in Ptf1a cKO pancreata. (C) Heat map of pathways that are significantly increased and decreased upon Ptf1a deletion. (D) Heat map of upstream pathways and regulators predicted to drive the observed changes in gene expression. Color scale is indicative of the -log p-value (significance). All analyses are based on a ±2.0-fold expression threshold. Full details of the data set and analyses can be found in the supplementary data files.DOI:http://dx.doi.org/10.7554/eLife.07125.016
Mentions: In order to investigate further the mechanism of ADM after loss of Ptf1a, we performed RNA-seq on whole pancreata from three control and three Ptf1a cKO mice, each of which received three doses of TM (0.25 mg/g) to induce maximal recombination 2 weeks prior to RNA extraction. Initial analysis of RNA-seq data sets by edgeR (Robinson et al., 2010), setting a false discovery rate (FDR) threshold of 0.05, identified significant changes in expression of over 3000 total genes (Figure 5A). Consistent with our immunostaining (Figure 4), among the most significantly downregulated mRNAs were Ptf1a (18.4-fold) and Cpa1 (5.45-fold), while Sox9 was significantly upregulated (4.61-fold) in Ptf1a cKO pancreata (Figure 5A). Additional downregulated mRNAs included a wide variety of digestive enzymes and other secreted proteins characteristic of the exocrine acinar phenotype, consistent with the long-standing hypothesis that they are directly regulated by PTF1A (Rose et al., 2001; MacDonald et al., in preparation).10.7554/eLife.07125.016Figure 5.Ptf1a suppresses fibroinflammatory pathways and oncogenic KRAS associated gene signatures.

Bottom Line: Loss of Ptf1a alone is sufficient to induce acinar-to-ductal metaplasia, potentiate inflammation, and induce a KRAS-permissive, PDAC-like gene expression profile.As a result, Ptf1a-deficient acinar cells are dramatically sensitized to KRAS transformation, and reduced Ptf1a greatly accelerates development of invasive PDAC.Together, these data indicate that cell differentiation regulators constitute a new tumor suppressive mechanism in the pancreas.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, University of Utah, Salt Lake City, United States.

ABSTRACT
Understanding the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) may provide therapeutic strategies for this deadly disease. Recently, we and others made the surprising finding that PDAC and its preinvasive precursors, pancreatic intraepithelial neoplasia (PanIN), arise via reprogramming of mature acinar cells. We therefore hypothesized that the master regulator of acinar differentiation, PTF1A, could play a central role in suppressing PDAC initiation. In this study, we demonstrate that PTF1A expression is lost in both mouse and human PanINs, and that this downregulation is functionally imperative in mice for acinar reprogramming by oncogenic KRAS. Loss of Ptf1a alone is sufficient to induce acinar-to-ductal metaplasia, potentiate inflammation, and induce a KRAS-permissive, PDAC-like gene expression profile. As a result, Ptf1a-deficient acinar cells are dramatically sensitized to KRAS transformation, and reduced Ptf1a greatly accelerates development of invasive PDAC. Together, these data indicate that cell differentiation regulators constitute a new tumor suppressive mechanism in the pancreas.

No MeSH data available.


Related in: MedlinePlus