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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

Liver metastases in KPC mice heterozygous for Ptf1a.(A) Gross image of a Pdx1-Cre; KrasG12D; Ptf1a+/− mouse harboring metastatic pancreatic cancer. White box highlights large liver metastasis. (B) Dissected lobe of the liver with pancreatic liver metastasis. (C) IHC for CLDN18 confirmed liver metastases in a subset of Pdx1-Cre; KrasG12D; p53+/−; Ptf1a+/− mice. (D) Gross image of Pdx1-Cre; KrasG12D; p53+/−; Ptf1a+/− mouse harboring metastatic PDAC. White box highlights liver metastasis.DOI:http://dx.doi.org/10.7554/eLife.07125.020
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fig7s1: Liver metastases in KPC mice heterozygous for Ptf1a.(A) Gross image of a Pdx1-Cre; KrasG12D; Ptf1a+/− mouse harboring metastatic pancreatic cancer. White box highlights large liver metastasis. (B) Dissected lobe of the liver with pancreatic liver metastasis. (C) IHC for CLDN18 confirmed liver metastases in a subset of Pdx1-Cre; KrasG12D; p53+/−; Ptf1a+/− mice. (D) Gross image of Pdx1-Cre; KrasG12D; p53+/−; Ptf1a+/− mouse harboring metastatic PDAC. White box highlights liver metastasis.DOI:http://dx.doi.org/10.7554/eLife.07125.020

Mentions: In humans, increased PanIN burden in early life is associated with familial risk of PDAC, suggesting that mutations driving genetic predisposition to PDAC act at the level of tumor initiation (Brune et al., 2006; Shi et al., 2009a). We therefore hypothesized that decreased Ptf1a dosage would promote cancer susceptibility by increasing the rate of PanIN initiation. Therefore, we utilized the well-characterized ‘KPC’ model of mouse PDAC in which heterozygous loss of p53 (official gene symbol Trp53) is added to the Pdx1-Cre; KrasLSL-G12D genotype (Hingorani et al., 2005; Rhim et al., 2012). As above, KPC mice (Pdx1-Cre; KrasLSL-G12D; p53lox/+) were generated on either Ptf1a+/+ or Ptf1aΔ/+ backgrounds, and animals were monitored for tumor-free survival. The results of Kaplan–Meier analysis showed that Ptf1a-heterozygous KPC mice developed PDAC much earlier than Ptf1a+/+ counterparts (Figure 7D, Log-rank test, p < 0.01). We observed prominent metastases to the liver in 3/9 Ptf1aΔ/+ KPC mice, but none in Ptf1a+/+ KPC controls (Figure 7—figure supplement 1). Importantly, despite the earlier onset of PDAC in KPC mice with Ptf1a heterozygosity, once tumors arose they were histologically indistinguishable between genotypes (Figure 7E–H). They contained classical features of human PDAC, including abundant fibrotic stroma surrounding CK19+ epithelial cells (Figure 7I,J) and substantial areas of necrosis. We therefore conclude that decreased Ptf1a gene dosage sensitizes pancreata to early KRAS-mediated PanIN initiation and rapid progression to PDAC.


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)

Liver metastases in KPC mice heterozygous for Ptf1a.(A) Gross image of a Pdx1-Cre; KrasG12D; Ptf1a+/− mouse harboring metastatic pancreatic cancer. White box highlights large liver metastasis. (B) Dissected lobe of the liver with pancreatic liver metastasis. (C) IHC for CLDN18 confirmed liver metastases in a subset of Pdx1-Cre; KrasG12D; p53+/−; Ptf1a+/− mice. (D) Gross image of Pdx1-Cre; KrasG12D; p53+/−; Ptf1a+/− mouse harboring metastatic PDAC. White box highlights liver metastasis.DOI:http://dx.doi.org/10.7554/eLife.07125.020
© Copyright Policy
Related In: Results  -  Collection

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

fig7s1: Liver metastases in KPC mice heterozygous for Ptf1a.(A) Gross image of a Pdx1-Cre; KrasG12D; Ptf1a+/− mouse harboring metastatic pancreatic cancer. White box highlights large liver metastasis. (B) Dissected lobe of the liver with pancreatic liver metastasis. (C) IHC for CLDN18 confirmed liver metastases in a subset of Pdx1-Cre; KrasG12D; p53+/−; Ptf1a+/− mice. (D) Gross image of Pdx1-Cre; KrasG12D; p53+/−; Ptf1a+/− mouse harboring metastatic PDAC. White box highlights liver metastasis.DOI:http://dx.doi.org/10.7554/eLife.07125.020
Mentions: In humans, increased PanIN burden in early life is associated with familial risk of PDAC, suggesting that mutations driving genetic predisposition to PDAC act at the level of tumor initiation (Brune et al., 2006; Shi et al., 2009a). We therefore hypothesized that decreased Ptf1a dosage would promote cancer susceptibility by increasing the rate of PanIN initiation. Therefore, we utilized the well-characterized ‘KPC’ model of mouse PDAC in which heterozygous loss of p53 (official gene symbol Trp53) is added to the Pdx1-Cre; KrasLSL-G12D genotype (Hingorani et al., 2005; Rhim et al., 2012). As above, KPC mice (Pdx1-Cre; KrasLSL-G12D; p53lox/+) were generated on either Ptf1a+/+ or Ptf1aΔ/+ backgrounds, and animals were monitored for tumor-free survival. The results of Kaplan–Meier analysis showed that Ptf1a-heterozygous KPC mice developed PDAC much earlier than Ptf1a+/+ counterparts (Figure 7D, Log-rank test, p < 0.01). We observed prominent metastases to the liver in 3/9 Ptf1aΔ/+ KPC mice, but none in Ptf1a+/+ KPC controls (Figure 7—figure supplement 1). Importantly, despite the earlier onset of PDAC in KPC mice with Ptf1a heterozygosity, once tumors arose they were histologically indistinguishable between genotypes (Figure 7E–H). They contained classical features of human PDAC, including abundant fibrotic stroma surrounding CK19+ epithelial cells (Figure 7I,J) and substantial areas of necrosis. We therefore conclude that decreased Ptf1a gene dosage sensitizes pancreata to early KRAS-mediated PanIN initiation and rapid progression to PDAC.

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