The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma
- University of Utah, United States
- University of Texas Southwestern Medical Center, United States
- Vanderbilt University Medical Center, 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. Here, 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.
Article and author information
Author details
Ethics
Animal experimentation: This study was performed according to institutional and National Institutes of Health guidelines for animal research (Guide for the Care and Use of Laboratory Animals), and followed protocols approved by the institutional animal care and use committees of the University of Utah (protocol #13-09009), University of Texas Southwestern Medical Center (protocol #2013-0008) and Vanderbilt University (protocol #M10/106).
Copyright
© 2015, Krah et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 5,506
- views
-
- 1,174
- downloads
-
- 127
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma
eLife 4:e07125.
https://doi.org/10.7554/eLife.07125
Further reading
-
- Developmental Biology
New research shows that the neural circuit responsible for stabilising gaze can develop in the absence of motor neurons, contrary to a long-standing model in the field.
-
- Developmental Biology
- Genetics and Genomics
O-GlcNAcylation is an essential intracellular protein modification mediated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Recently, missense mutations in OGT have been linked to intellectual disability, indicating that this modification is important for the development and functioning of the nervous system. However, the processes that are most sensitive to perturbations in O-GlcNAcylation remain to be identified. Here, we uncover quantifiable phenotypes in the fruit fly Drosophila melanogaster carrying a patient-derived OGT mutation in the catalytic domain. Hypo-O-GlcNAcylation leads to defects in synaptogenesis and reduced sleep stability. Both these phenotypes can be partially rescued by genetically or chemically targeting OGA, suggesting that a balance of OGT/OGA activity is required for normal neuronal development and function.
