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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

Mucinous metaplasia associated with hyperactive MEK-ERK signaling in caerulein-treated Ptf1a cKO pancreata.(A, B) IHC for the PanIN markers Claudin-18 (A) and MUC5ac (B) in caerulein-treated Ptf1a cKO with corresponding positive and negative controls. Green arrows indicate weakly Claudin-18 positive or Muc5ac positive lesions and red arrows indicate Claudin-18/Muc5ac negative metaplasia. (C–F) IHC for phosphorylated-ERK (p-ERK) on control and Ptf1a cKO pancreata 1 week following caerulein treatment. Enlarged boxed area highlights mucinous metaplasia-like lesions from caerulein-treated Ptf1a cKO pancreata with strong nuclear p-ERK signal. Scale bars: 200 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.018
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fig6s1: Mucinous metaplasia associated with hyperactive MEK-ERK signaling in caerulein-treated Ptf1a cKO pancreata.(A, B) IHC for the PanIN markers Claudin-18 (A) and MUC5ac (B) in caerulein-treated Ptf1a cKO with corresponding positive and negative controls. Green arrows indicate weakly Claudin-18 positive or Muc5ac positive lesions and red arrows indicate Claudin-18/Muc5ac negative metaplasia. (C–F) IHC for phosphorylated-ERK (p-ERK) on control and Ptf1a cKO pancreata 1 week following caerulein treatment. Enlarged boxed area highlights mucinous metaplasia-like lesions from caerulein-treated Ptf1a cKO pancreata with strong nuclear p-ERK signal. Scale bars: 200 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.018

Mentions: To test this hypothesis in vivo, we deleted Ptf1a via high-dose TM administration (three doses of 0.17 mg/g), which induced a recombination rate of ∼65% (Figure 4—figure supplement 1). At 1 week post-TM, acute pancreatitis was induced by two consecutive days of treatment with the secretagogue caerulein, as previously described (Jensen et al., 2005; Keefe et al., 2012), and pancreata were harvested 1 week later (Figure 6A). As a control for caerulein injections, additional TM-treated Ptf1a cKO and control mice were administered saline vehicle alone. As previously reported, control mice recovered from caerulein treatment and were indistinguishable from saline-injected controls after 1 week (Figure 6B–D). In contrast, Ptf1a cKO mice subjected to caerulein-induced pancreatitis exhibited widespread acinar atrophy, persistent inflammation, fibrotic stroma, and the appearance of mucinous metaplastic structures (Figure 6E,F). These abnormal ductules were Alcian Blue-reactive, similar to PanINs (Figure 6G), although staining for the PanIN-specific markers CLDN18 and MUC5AC was observed in only rare and isolated lesions (Figure 6—figure supplement 1A,B). Consistent with the overall distorted histology (Figure 6E) and atrophy (Figure 6H) of caerulein-treated Ptf1a cKO mice, no normal amylase+ acinar clusters could be detected in these pancreata, in contrast to controls (Figure 6I–L). Acinar-derived EYFP+ cells in caerulein-treated Ptf1a cKO pancreata were instead integrated within CK19+ duct-like structures, suggesting that pancreatitis synergizes with loss of Ptf1a to cause a rapid loss of acinar gene expression and complete reprogramming to a duct-like fate (Figure 6I–L).10.7554/eLife.07125.017Figure 6.Ptf1a is necessary for acinar cell regeneration and suppression of dysplasia following induced pancreatitis.


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)

Mucinous metaplasia associated with hyperactive MEK-ERK signaling in caerulein-treated Ptf1a cKO pancreata.(A, B) IHC for the PanIN markers Claudin-18 (A) and MUC5ac (B) in caerulein-treated Ptf1a cKO with corresponding positive and negative controls. Green arrows indicate weakly Claudin-18 positive or Muc5ac positive lesions and red arrows indicate Claudin-18/Muc5ac negative metaplasia. (C–F) IHC for phosphorylated-ERK (p-ERK) on control and Ptf1a cKO pancreata 1 week following caerulein treatment. Enlarged boxed area highlights mucinous metaplasia-like lesions from caerulein-treated Ptf1a cKO pancreata with strong nuclear p-ERK signal. Scale bars: 200 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.018
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4536747&req=5

fig6s1: Mucinous metaplasia associated with hyperactive MEK-ERK signaling in caerulein-treated Ptf1a cKO pancreata.(A, B) IHC for the PanIN markers Claudin-18 (A) and MUC5ac (B) in caerulein-treated Ptf1a cKO with corresponding positive and negative controls. Green arrows indicate weakly Claudin-18 positive or Muc5ac positive lesions and red arrows indicate Claudin-18/Muc5ac negative metaplasia. (C–F) IHC for phosphorylated-ERK (p-ERK) on control and Ptf1a cKO pancreata 1 week following caerulein treatment. Enlarged boxed area highlights mucinous metaplasia-like lesions from caerulein-treated Ptf1a cKO pancreata with strong nuclear p-ERK signal. Scale bars: 200 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.018
Mentions: To test this hypothesis in vivo, we deleted Ptf1a via high-dose TM administration (three doses of 0.17 mg/g), which induced a recombination rate of ∼65% (Figure 4—figure supplement 1). At 1 week post-TM, acute pancreatitis was induced by two consecutive days of treatment with the secretagogue caerulein, as previously described (Jensen et al., 2005; Keefe et al., 2012), and pancreata were harvested 1 week later (Figure 6A). As a control for caerulein injections, additional TM-treated Ptf1a cKO and control mice were administered saline vehicle alone. As previously reported, control mice recovered from caerulein treatment and were indistinguishable from saline-injected controls after 1 week (Figure 6B–D). In contrast, Ptf1a cKO mice subjected to caerulein-induced pancreatitis exhibited widespread acinar atrophy, persistent inflammation, fibrotic stroma, and the appearance of mucinous metaplastic structures (Figure 6E,F). These abnormal ductules were Alcian Blue-reactive, similar to PanINs (Figure 6G), although staining for the PanIN-specific markers CLDN18 and MUC5AC was observed in only rare and isolated lesions (Figure 6—figure supplement 1A,B). Consistent with the overall distorted histology (Figure 6E) and atrophy (Figure 6H) of caerulein-treated Ptf1a cKO mice, no normal amylase+ acinar clusters could be detected in these pancreata, in contrast to controls (Figure 6I–L). Acinar-derived EYFP+ cells in caerulein-treated Ptf1a cKO pancreata were instead integrated within CK19+ duct-like structures, suggesting that pancreatitis synergizes with loss of Ptf1a to cause a rapid loss of acinar gene expression and complete reprogramming to a duct-like fate (Figure 6I–L).10.7554/eLife.07125.017Figure 6.Ptf1a is necessary for acinar cell regeneration and suppression of dysplasia following induced pancreatitis.

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