Limits...
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 expression in rare epithelial cells of human PanINs.(A) IHC for PTF1A from a KrasG12D mouse pancreas 9 months after TM administration (0.17 mg/g). (B–E) IHC for PTF1A on human pathology samples. Black arrows indicate normal acinar cells expressing PTF1A; green arrows highlight PanIN epithelial cells that do not express PTF1A; red arrows indicate rare PanIN epithelial cells that retain trace PTF1A expression. Scale bars: (A–C) 25 μm; (D) 100 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.004
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4536747&req=5

fig1s1: PTF1A expression in rare epithelial cells of human PanINs.(A) IHC for PTF1A from a KrasG12D mouse pancreas 9 months after TM administration (0.17 mg/g). (B–E) IHC for PTF1A on human pathology samples. Black arrows indicate normal acinar cells expressing PTF1A; green arrows highlight PanIN epithelial cells that do not express PTF1A; red arrows indicate rare PanIN epithelial cells that retain trace PTF1A expression. Scale bars: (A–C) 25 μm; (D) 100 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.004

Mentions: We have previously demonstrated that Ptf1a expression is lost when activated Notch and KrasG12D work synergistically to reprogram acinar cells into PanINs (De La et al., 2008). Given that Ptf1a is a central regulator of acinar cell gene expression, we hypothesized that this transcription factor should also be downregulated when acinar cells are transformed by oncogenic KrasG12D alone, as well as in human PanINs. To test this hypothesis, we activated KrasG12D specifically in acinar cells using a tamoxifen-inducible Cre expressed by the endogenous Ptf1a locus (Ptf1aCreERT) (Kopinke et al., 2012; Pan et al., 2013). Like the widely used Ptf1aCre allele (Kawaguchi et al., 2002), Ptf1aCreERT is a ‘knock-in/knock-out’ allele, and therefore, these mice are functionally heterozygous for Ptf1a. We induced KrasG12D expression at 6 weeks of age and harvested pancreata 9 months later. While most acini appeared histologically normal and resistant to KRAS-mediated transformation (Figure 1A), there was intermittent PanIN formation throughout the pancreas (Figure 1B), as previously reported (Kopp et al., 2012). By immunohistochemistry (IHC), normal acinar cells in these tissues exhibited robust nuclear PTF1A (Figure 1C); however, PTF1A was strongly decreased or absent in all acinar-derived PanIN lesions (Figure 1D). To extend these studies to human pancreatic cancer initiation, we stained pathological specimens (n = 4) containing both normal acinar tissue (Figure 1E) and PanIN lesions (Figure 1F). As observed in the KrasG12D mouse model, normal acini exhibited a strong PTF1A nuclear signal (Figure 1G), but PTF1A was largely absent from epithelial cell nuclei within PanINs (Figure 1H). In a small fraction of human PanINs, low levels of PTF1A were observed in a subset of epithelial cells (Figure 1—figure supplement 1). Residual PTF1A expression is consistent with the finding that approximately one-third of human PDAC samples express low levels of acinar-specific genes (Collisson et al., 2011).10.7554/eLife.07125.003Figure 1.PTF1A is downregulated in PanINs from mice and humans.


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 expression in rare epithelial cells of human PanINs.(A) IHC for PTF1A from a KrasG12D mouse pancreas 9 months after TM administration (0.17 mg/g). (B–E) IHC for PTF1A on human pathology samples. Black arrows indicate normal acinar cells expressing PTF1A; green arrows highlight PanIN epithelial cells that do not express PTF1A; red arrows indicate rare PanIN epithelial cells that retain trace PTF1A expression. Scale bars: (A–C) 25 μm; (D) 100 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.004
© Copyright Policy
Related In: Results  -  Collection

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

fig1s1: PTF1A expression in rare epithelial cells of human PanINs.(A) IHC for PTF1A from a KrasG12D mouse pancreas 9 months after TM administration (0.17 mg/g). (B–E) IHC for PTF1A on human pathology samples. Black arrows indicate normal acinar cells expressing PTF1A; green arrows highlight PanIN epithelial cells that do not express PTF1A; red arrows indicate rare PanIN epithelial cells that retain trace PTF1A expression. Scale bars: (A–C) 25 μm; (D) 100 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.004
Mentions: We have previously demonstrated that Ptf1a expression is lost when activated Notch and KrasG12D work synergistically to reprogram acinar cells into PanINs (De La et al., 2008). Given that Ptf1a is a central regulator of acinar cell gene expression, we hypothesized that this transcription factor should also be downregulated when acinar cells are transformed by oncogenic KrasG12D alone, as well as in human PanINs. To test this hypothesis, we activated KrasG12D specifically in acinar cells using a tamoxifen-inducible Cre expressed by the endogenous Ptf1a locus (Ptf1aCreERT) (Kopinke et al., 2012; Pan et al., 2013). Like the widely used Ptf1aCre allele (Kawaguchi et al., 2002), Ptf1aCreERT is a ‘knock-in/knock-out’ allele, and therefore, these mice are functionally heterozygous for Ptf1a. We induced KrasG12D expression at 6 weeks of age and harvested pancreata 9 months later. While most acini appeared histologically normal and resistant to KRAS-mediated transformation (Figure 1A), there was intermittent PanIN formation throughout the pancreas (Figure 1B), as previously reported (Kopp et al., 2012). By immunohistochemistry (IHC), normal acinar cells in these tissues exhibited robust nuclear PTF1A (Figure 1C); however, PTF1A was strongly decreased or absent in all acinar-derived PanIN lesions (Figure 1D). To extend these studies to human pancreatic cancer initiation, we stained pathological specimens (n = 4) containing both normal acinar tissue (Figure 1E) and PanIN lesions (Figure 1F). As observed in the KrasG12D mouse model, normal acini exhibited a strong PTF1A nuclear signal (Figure 1G), but PTF1A was largely absent from epithelial cell nuclei within PanINs (Figure 1H). In a small fraction of human PanINs, low levels of PTF1A were observed in a subset of epithelial cells (Figure 1—figure supplement 1). Residual PTF1A expression is consistent with the finding that approximately one-third of human PDAC samples express low levels of acinar-specific genes (Collisson et al., 2011).10.7554/eLife.07125.003Figure 1.PTF1A is downregulated in PanINs from mice and humans.

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