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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

Schematic of mouse alleles used in this study.Schematic representations of the alleles present in the genotypes referred to, in shorthand, as control, Ptf1a cKO, KrasG12D and Ptf1a cKO; KrasG12D (see Table 1 for additional details).DOI:http://dx.doi.org/10.7554/eLife.07125.007
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fig2s1: Schematic of mouse alleles used in this study.Schematic representations of the alleles present in the genotypes referred to, in shorthand, as control, Ptf1a cKO, KrasG12D and Ptf1a cKO; KrasG12D (see Table 1 for additional details).DOI:http://dx.doi.org/10.7554/eLife.07125.007

Mentions: In order to determine whether PTF1A downregulation was a functionally important step in PanIN initiation, or a side effect of acinar cell transformation itself, we used an inducible system to delete Ptf1a both in the absence and presence of oncogenic KrasG12D. In this model, we combined the Ptf1aCreERT allele, which does not express PTF1A protein, with a ‘floxed’ Ptf1a allele, to generate Ptf1a conditional knock-out (cKO) mice of the genotype Ptf1aCreERT/lox. We also crossed KrasLSL-G12D onto this Ptf1a cKO background. Negative control littermates were Ptf1a heterozygous (Ptf1aCreERT/+) without oncogenic Kras. An additional control group, representing baseline PanIN initiation in the presence of wild-type PTF1A, consisted of Ptf1aCreERT/+; KrasLSL-G12D littermates (henceforth referred to as KrasG12D mice). All inducible-Cre mice also contained a R26REYFP reporter (Srinivas et al., 2001), which allowed monitoring of the frequency of Cre-mediated recombination and lineage-tracing of the fate of recombined acinar cells. Table 1 summarizes the genotypes of mice used throughout this study; Figure 2—figure supplement 1 schematically depicts the alleles in each genotype.10.7554/eLife.07125.005Table 1.


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)

Schematic of mouse alleles used in this study.Schematic representations of the alleles present in the genotypes referred to, in shorthand, as control, Ptf1a cKO, KrasG12D and Ptf1a cKO; KrasG12D (see Table 1 for additional details).DOI:http://dx.doi.org/10.7554/eLife.07125.007
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4536747&req=5

fig2s1: Schematic of mouse alleles used in this study.Schematic representations of the alleles present in the genotypes referred to, in shorthand, as control, Ptf1a cKO, KrasG12D and Ptf1a cKO; KrasG12D (see Table 1 for additional details).DOI:http://dx.doi.org/10.7554/eLife.07125.007
Mentions: In order to determine whether PTF1A downregulation was a functionally important step in PanIN initiation, or a side effect of acinar cell transformation itself, we used an inducible system to delete Ptf1a both in the absence and presence of oncogenic KrasG12D. In this model, we combined the Ptf1aCreERT allele, which does not express PTF1A protein, with a ‘floxed’ Ptf1a allele, to generate Ptf1a conditional knock-out (cKO) mice of the genotype Ptf1aCreERT/lox. We also crossed KrasLSL-G12D onto this Ptf1a cKO background. Negative control littermates were Ptf1a heterozygous (Ptf1aCreERT/+) without oncogenic Kras. An additional control group, representing baseline PanIN initiation in the presence of wild-type PTF1A, consisted of Ptf1aCreERT/+; KrasLSL-G12D littermates (henceforth referred to as KrasG12D mice). All inducible-Cre mice also contained a R26REYFP reporter (Srinivas et al., 2001), which allowed monitoring of the frequency of Cre-mediated recombination and lineage-tracing of the fate of recombined acinar cells. Table 1 summarizes the genotypes of mice used throughout this study; Figure 2—figure supplement 1 schematically depicts the alleles in each genotype.10.7554/eLife.07125.005Table 1.

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