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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

Acinar-ductal reprogramming in 3D culture.(A, B) Brightfield images of acinarderived ductal cysts from (A) KrasG12D and (B) Ptf1a cKO; KrasG12D mice, after 3 days of culture in collagen gel. (C) Quantification of the maximum diameter of acinar-derived cysts from mice of indicated genotypes (n = 3 mice per genotype). For each mouse, >10 randomly selected fields were photographed, and each cyst within the image was measured at its maximum diameter. Scale bars are 400 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.011
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fig3s2: Acinar-ductal reprogramming in 3D culture.(A, B) Brightfield images of acinarderived ductal cysts from (A) KrasG12D and (B) Ptf1a cKO; KrasG12D mice, after 3 days of culture in collagen gel. (C) Quantification of the maximum diameter of acinar-derived cysts from mice of indicated genotypes (n = 3 mice per genotype). For each mouse, >10 randomly selected fields were photographed, and each cyst within the image was measured at its maximum diameter. Scale bars are 400 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.011

Mentions: In order to determine the acinar cell-intrinsic consequences of Ptf1a deletion, we used a 3D culture system in which acini can undergo metaplasia into ductal cysts in response to mutant Kras or EGF receptor (EGFR) ligand stimulation, without the influence of other cell types (Means et al., 2005; Ardito et al., 2012). To induce widespread, acinar-specific Kras activation and/or Ptf1a deletion, we treated mice with three daily doses of tamoxifen at 0.25 mg/ml, a treatment paradigm that we found to drive widespread recombination (see below). Acinar cell clusters from control, Ptf1a cKO, KrasG12D, and Ptf1a cKO; KrasG12D were isolated at 3 days after the final TM dose, prior to the appearance of any histological abnormalities, and embedded in a collagen matrix, as previously described (Means et al., 2005; Ardito et al., 2012). Neither control nor Ptf1a cKO acinar clusters underwent spontaneous cyst conversion, in the absence of added growth factors, implying that loss of Ptf1a is not sufficient for acinar-ductal reprogramming. As expected, acini of both genotypes generated CK19+ ductal cysts in response to the EGFR ligand TGFα (data not shown). By contrast, KrasG12D activation was sufficient for generation of acinar-derived cysts; importantly, Ptf1a cKO; KrasG12D acini formed significantly larger cysts than those derived from KrasG12D pancreata (Figure 3—figure supplement 2). These results are consistent with our in vivo data and suggest that acinar cell loss of Ptf1a enhances KRAS-mediated transformation independent of effects on the stromal microenvironment.


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)

Acinar-ductal reprogramming in 3D culture.(A, B) Brightfield images of acinarderived ductal cysts from (A) KrasG12D and (B) Ptf1a cKO; KrasG12D mice, after 3 days of culture in collagen gel. (C) Quantification of the maximum diameter of acinar-derived cysts from mice of indicated genotypes (n = 3 mice per genotype). For each mouse, >10 randomly selected fields were photographed, and each cyst within the image was measured at its maximum diameter. Scale bars are 400 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.011
© Copyright Policy
Related In: Results  -  Collection

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

fig3s2: Acinar-ductal reprogramming in 3D culture.(A, B) Brightfield images of acinarderived ductal cysts from (A) KrasG12D and (B) Ptf1a cKO; KrasG12D mice, after 3 days of culture in collagen gel. (C) Quantification of the maximum diameter of acinar-derived cysts from mice of indicated genotypes (n = 3 mice per genotype). For each mouse, >10 randomly selected fields were photographed, and each cyst within the image was measured at its maximum diameter. Scale bars are 400 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.011
Mentions: In order to determine the acinar cell-intrinsic consequences of Ptf1a deletion, we used a 3D culture system in which acini can undergo metaplasia into ductal cysts in response to mutant Kras or EGF receptor (EGFR) ligand stimulation, without the influence of other cell types (Means et al., 2005; Ardito et al., 2012). To induce widespread, acinar-specific Kras activation and/or Ptf1a deletion, we treated mice with three daily doses of tamoxifen at 0.25 mg/ml, a treatment paradigm that we found to drive widespread recombination (see below). Acinar cell clusters from control, Ptf1a cKO, KrasG12D, and Ptf1a cKO; KrasG12D were isolated at 3 days after the final TM dose, prior to the appearance of any histological abnormalities, and embedded in a collagen matrix, as previously described (Means et al., 2005; Ardito et al., 2012). Neither control nor Ptf1a cKO acinar clusters underwent spontaneous cyst conversion, in the absence of added growth factors, implying that loss of Ptf1a is not sufficient for acinar-ductal reprogramming. As expected, acini of both genotypes generated CK19+ ductal cysts in response to the EGFR ligand TGFα (data not shown). By contrast, KrasG12D activation was sufficient for generation of acinar-derived cysts; importantly, Ptf1a cKO; KrasG12D acini formed significantly larger cysts than those derived from KrasG12D pancreata (Figure 3—figure supplement 2). These results are consistent with our in vivo data and suggest that acinar cell loss of Ptf1a enhances KRAS-mediated transformation independent of effects on the stromal microenvironment.

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