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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

High-dose tamoxifen administration does not induce pancreatitis.(A–D) Lowand (A′–D′) high-magnification H&E staining of wild-type pancreata, fixed 24 hr after indicated treatment. (E–H) Immunofluorescence for CK19 (red), CD45 (green) and DAPI (blue), highlighting inflammatory cells in the exocrine pancreas. Scale bars: (A–D) 200 μm, (A′–D′) 100 μm, (E–H) 50 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.015
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fig4s3: High-dose tamoxifen administration does not induce pancreatitis.(A–D) Lowand (A′–D′) high-magnification H&E staining of wild-type pancreata, fixed 24 hr after indicated treatment. (E–H) Immunofluorescence for CK19 (red), CD45 (green) and DAPI (blue), highlighting inflammatory cells in the exocrine pancreas. Scale bars: (A–D) 200 μm, (A′–D′) 100 μm, (E–H) 50 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.015

Mentions: 2 weeks following high-dose TM, Ptf1a cKO pancreata were less than half the mass of their control counterparts (Figure 4B). Immunofluorescence revealed that while nearly all EYFP+ acinar cells expressed the acinar marker carboxypeptidase A1 (CPA1) in controls, this marker was lost from approximately 15% of EYFP+ cells in Ptf1a cKO tissues, indicating loss of the normal differentiation state (Figure 4C–E). Histologically, Ptf1a cKO pancreata exhibited extensive acinar disorganization and dilation as well as sporadic upregulation of CK19 within acinar structures, suggestive of early stages of ADM (Figure 4F–I). CK19+ acinar cells (defined by EYFP co-expression) were consistently surrounded by CD45+ leukocytes (Figure 4—figure supplement 2A–C), consistent with an intimate association between metaplasia and inflammatory cell recruitment (Liou et al., 2013; Murtaugh and Keefe, 2015). Nonetheless, Ptf1a cKO pancreata did not exhibit a general pancreatitis phenotype (Figure 4—figure supplement 2A–C) nor did they exhibit a detectable increase in epithelial cell apoptosis (Figure 4—figure supplement 2D–F). In addition, we found that treatment of wild-type mice with high-dose TM was not sufficient to induce pancreatic inflammation (Figure 4—figure supplement 3), suggesting that the stronger phenotype of high-dose Ptf1a cKO mice, relative to low-dose, was not due to stimulation of ADM by non-specific tissue damage.


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)

High-dose tamoxifen administration does not induce pancreatitis.(A–D) Lowand (A′–D′) high-magnification H&E staining of wild-type pancreata, fixed 24 hr after indicated treatment. (E–H) Immunofluorescence for CK19 (red), CD45 (green) and DAPI (blue), highlighting inflammatory cells in the exocrine pancreas. Scale bars: (A–D) 200 μm, (A′–D′) 100 μm, (E–H) 50 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.015
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fig4s3: High-dose tamoxifen administration does not induce pancreatitis.(A–D) Lowand (A′–D′) high-magnification H&E staining of wild-type pancreata, fixed 24 hr after indicated treatment. (E–H) Immunofluorescence for CK19 (red), CD45 (green) and DAPI (blue), highlighting inflammatory cells in the exocrine pancreas. Scale bars: (A–D) 200 μm, (A′–D′) 100 μm, (E–H) 50 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.015
Mentions: 2 weeks following high-dose TM, Ptf1a cKO pancreata were less than half the mass of their control counterparts (Figure 4B). Immunofluorescence revealed that while nearly all EYFP+ acinar cells expressed the acinar marker carboxypeptidase A1 (CPA1) in controls, this marker was lost from approximately 15% of EYFP+ cells in Ptf1a cKO tissues, indicating loss of the normal differentiation state (Figure 4C–E). Histologically, Ptf1a cKO pancreata exhibited extensive acinar disorganization and dilation as well as sporadic upregulation of CK19 within acinar structures, suggestive of early stages of ADM (Figure 4F–I). CK19+ acinar cells (defined by EYFP co-expression) were consistently surrounded by CD45+ leukocytes (Figure 4—figure supplement 2A–C), consistent with an intimate association between metaplasia and inflammatory cell recruitment (Liou et al., 2013; Murtaugh and Keefe, 2015). Nonetheless, Ptf1a cKO pancreata did not exhibit a general pancreatitis phenotype (Figure 4—figure supplement 2A–C) nor did they exhibit a detectable increase in epithelial cell apoptosis (Figure 4—figure supplement 2D–F). In addition, we found that treatment of wild-type mice with high-dose TM was not sufficient to induce pancreatic inflammation (Figure 4—figure supplement 3), suggesting that the stronger phenotype of high-dose Ptf1a cKO mice, relative to low-dose, was not due to stimulation of ADM by non-specific tissue damage.

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