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

Microenvironmental remodeling in Ptf1a cKO; KrasG12D pancreata.Pancreata were harvested 2 weeks following TM administration (0.17 mg/g) to mice of the indicated genotypes. (A–D) Immunofluorescence for the PanIN marker CLDN18 (red), and the leukocyte marker CD45 (green), revealing association of leukocytes with PanINs in Ptf1a cKO; KrasG12D. (E–H) IHC for α-SMA, highlighting the activation of pancreatic stellate cells in Ptf1a cKO; KrasG12D pancreata. (I–L) Sirius Red staining, highlighting widespread fibrosis in Ptf1a cKO; KrasG12D. Scale bars: (A–D) 50 μm, (E–L) 200 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.010
© Copyright Policy
Related In: Results  -  Collection

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

fig3s1: Microenvironmental remodeling in Ptf1a cKO; KrasG12D pancreata.Pancreata were harvested 2 weeks following TM administration (0.17 mg/g) to mice of the indicated genotypes. (A–D) Immunofluorescence for the PanIN marker CLDN18 (red), and the leukocyte marker CD45 (green), revealing association of leukocytes with PanINs in Ptf1a cKO; KrasG12D. (E–H) IHC for α-SMA, highlighting the activation of pancreatic stellate cells in Ptf1a cKO; KrasG12D pancreata. (I–L) Sirius Red staining, highlighting widespread fibrosis in Ptf1a cKO; KrasG12D. Scale bars: (A–D) 50 μm, (E–L) 200 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.010

Mentions: Interestingly, this level of Ptf1a deletion alone did not produce ADM or other histologically detectable effects at 2 weeks post-TM, compared to control mice (Figure 3B,C). While KrasG12D pancreata exhibited few or no PanINs at this time point, there was widespread induction of ADM, leukocyte infiltration, fibrosis, and PanIN initiation in Ptf1a cKO; KrasG12D pancreata (Figure 3D,E and Figure 3—figure supplement 1). We further confirmed that acinar-derived ADM and PanINs were being reprogrammed to a duct-like fate based on expression of the ductal transcription factor SOX9. While only normal ducts expressed SOX9 in control pancreata, PanINs and ADM in Ptf1a cKO; KrasG12D were SOX9+ at 2 weeks post-TM (Figure 3F–I). These data are consistent with a recent study indicating that Sox9 is necessary but not sufficient for the earliest stages of mouse PanIN initiation (Kopp et al., 2012).


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)

Microenvironmental remodeling in Ptf1a cKO; KrasG12D pancreata.Pancreata were harvested 2 weeks following TM administration (0.17 mg/g) to mice of the indicated genotypes. (A–D) Immunofluorescence for the PanIN marker CLDN18 (red), and the leukocyte marker CD45 (green), revealing association of leukocytes with PanINs in Ptf1a cKO; KrasG12D. (E–H) IHC for α-SMA, highlighting the activation of pancreatic stellate cells in Ptf1a cKO; KrasG12D pancreata. (I–L) Sirius Red staining, highlighting widespread fibrosis in Ptf1a cKO; KrasG12D. Scale bars: (A–D) 50 μm, (E–L) 200 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.010
© Copyright Policy
Related In: Results  -  Collection

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

fig3s1: Microenvironmental remodeling in Ptf1a cKO; KrasG12D pancreata.Pancreata were harvested 2 weeks following TM administration (0.17 mg/g) to mice of the indicated genotypes. (A–D) Immunofluorescence for the PanIN marker CLDN18 (red), and the leukocyte marker CD45 (green), revealing association of leukocytes with PanINs in Ptf1a cKO; KrasG12D. (E–H) IHC for α-SMA, highlighting the activation of pancreatic stellate cells in Ptf1a cKO; KrasG12D pancreata. (I–L) Sirius Red staining, highlighting widespread fibrosis in Ptf1a cKO; KrasG12D. Scale bars: (A–D) 50 μm, (E–L) 200 μm.DOI:http://dx.doi.org/10.7554/eLife.07125.010
Mentions: Interestingly, this level of Ptf1a deletion alone did not produce ADM or other histologically detectable effects at 2 weeks post-TM, compared to control mice (Figure 3B,C). While KrasG12D pancreata exhibited few or no PanINs at this time point, there was widespread induction of ADM, leukocyte infiltration, fibrosis, and PanIN initiation in Ptf1a cKO; KrasG12D pancreata (Figure 3D,E and Figure 3—figure supplement 1). We further confirmed that acinar-derived ADM and PanINs were being reprogrammed to a duct-like fate based on expression of the ductal transcription factor SOX9. While only normal ducts expressed SOX9 in control pancreata, PanINs and ADM in Ptf1a cKO; KrasG12D were SOX9+ at 2 weeks post-TM (Figure 3F–I). These data are consistent with a recent study indicating that Sox9 is necessary but not sufficient for the earliest stages of mouse PanIN initiation (Kopp et al., 2012).

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