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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

Cre-mediated recombination rates following high-dose tamoxifen treatment.(A) 6–8 week old mice were administered 0.17 mg/g TM on three consecutive days, and pancreata were harvested 1 week later. (B, C) Immunofluorescence for amylase (red) and the Cre reporter R26REYFP (green) in TM-treated pancreata of the indicated genotypes. (D) The proportion of EYFP expression within amylase+ acinar cells was quantified for all genotypes. No significant difference was observed between groups (n = 3–4 per genotype). Scale bar: 100 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.013
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fig4s1: Cre-mediated recombination rates following high-dose tamoxifen treatment.(A) 6–8 week old mice were administered 0.17 mg/g TM on three consecutive days, and pancreata were harvested 1 week later. (B, C) Immunofluorescence for amylase (red) and the Cre reporter R26REYFP (green) in TM-treated pancreata of the indicated genotypes. (D) The proportion of EYFP expression within amylase+ acinar cells was quantified for all genotypes. No significant difference was observed between groups (n = 3–4 per genotype). Scale bar: 100 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.013

Mentions: As we were surprised that a moderate level of acinar cell recombination (∼25%) failed to produce an overt, short-term phenotype in Ptf1a cKO pancreata (Figure 3), we tested if more pervasive deletion of Ptf1a would produce a more robust reprogramming phenotype. Control and Ptf1a cKO mice were administered a higher dose of TM (0.25 mg/g) by oral gavage on three consecutive days (a net 4.5-fold higher dose than previously) and were harvested 2 weeks later (Figure 4A). Quantification of EYFP+ acinar cells following this TM regimen demonstrated a recombination frequency of ∼65% (Figure 4—figure supplement 1). Additionally, we quantified the number of PTF1A-deficient acinar cells at 3 days after the final TM gavage, and found that only ∼15% of all pancreatic cells retained nuclear PTF1A, compared with ∼82% in TM-untreated controls (Figure 2—figure supplement 2). As with low-dose TM, described above, the majority (>90%) of EYFP+ cells were PTF1A-negative at 3 days post-TM, confirming that EYFP expression highlights acinar cells deleted for Ptf1a (Figure 2—figure supplement 2). The apparently greater extent of PTF1A ablation, relative to EYFP activation, may imply the existence of Ptf1a-deleted cells within the EYFP-negative population; such an observation would be consistent with previous evidence of locus-specific Cre deletion efficiencies (Liu et al., 2013).10.7554/eLife.07125.012Figure 4.Widespread loss of Ptf1a promotes rapid acinar-to-ductal metaplasia.


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)

Cre-mediated recombination rates following high-dose tamoxifen treatment.(A) 6–8 week old mice were administered 0.17 mg/g TM on three consecutive days, and pancreata were harvested 1 week later. (B, C) Immunofluorescence for amylase (red) and the Cre reporter R26REYFP (green) in TM-treated pancreata of the indicated genotypes. (D) The proportion of EYFP expression within amylase+ acinar cells was quantified for all genotypes. No significant difference was observed between groups (n = 3–4 per genotype). Scale bar: 100 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.013
© Copyright Policy
Related In: Results  -  Collection

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

fig4s1: Cre-mediated recombination rates following high-dose tamoxifen treatment.(A) 6–8 week old mice were administered 0.17 mg/g TM on three consecutive days, and pancreata were harvested 1 week later. (B, C) Immunofluorescence for amylase (red) and the Cre reporter R26REYFP (green) in TM-treated pancreata of the indicated genotypes. (D) The proportion of EYFP expression within amylase+ acinar cells was quantified for all genotypes. No significant difference was observed between groups (n = 3–4 per genotype). Scale bar: 100 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.013
Mentions: As we were surprised that a moderate level of acinar cell recombination (∼25%) failed to produce an overt, short-term phenotype in Ptf1a cKO pancreata (Figure 3), we tested if more pervasive deletion of Ptf1a would produce a more robust reprogramming phenotype. Control and Ptf1a cKO mice were administered a higher dose of TM (0.25 mg/g) by oral gavage on three consecutive days (a net 4.5-fold higher dose than previously) and were harvested 2 weeks later (Figure 4A). Quantification of EYFP+ acinar cells following this TM regimen demonstrated a recombination frequency of ∼65% (Figure 4—figure supplement 1). Additionally, we quantified the number of PTF1A-deficient acinar cells at 3 days after the final TM gavage, and found that only ∼15% of all pancreatic cells retained nuclear PTF1A, compared with ∼82% in TM-untreated controls (Figure 2—figure supplement 2). As with low-dose TM, described above, the majority (>90%) of EYFP+ cells were PTF1A-negative at 3 days post-TM, confirming that EYFP expression highlights acinar cells deleted for Ptf1a (Figure 2—figure supplement 2). The apparently greater extent of PTF1A ablation, relative to EYFP activation, may imply the existence of Ptf1a-deleted cells within the EYFP-negative population; such an observation would be consistent with previous evidence of locus-specific Cre deletion efficiencies (Liu et al., 2013).10.7554/eLife.07125.012Figure 4.Widespread loss of Ptf1a promotes rapid acinar-to-ductal metaplasia.

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