Loss of Pancreatic E-Cadherin Causes Pancreatitis-Like Changes and Contributes to Carcinogenesis.

Abstract

BACKGROUND & AIMS:

E-cadherin (Cdh1) is a key molecule for adherence required for maintenance of structural homeostasis. Loss of E-cadherin leads to poor prognosis and the development of resistance to chemotherapy in pancreatic cancer. Here, we evaluated the physiological and pathologic roles of E-cadherin in the pancreas.

METHODS:

We crossbred Ptf1a-Cre mice with Cdh1f/f mice to examine the physiological roles of E-cadherin in the pancreas. In addition, we crossbred these mice with LSL-KrasG12D/+ mice (PKC) to investigate the pathologic roles of E-cadherin. We also generated a tamoxifen-inducible system (Ptf1a-CreERT model). Organoids derived from these models using lentiviral transduction were analyzed for immunohistochemical features. Established cell lines from these organoids were analyzed for migratory and invasive activities as well as gene expression by complementary DNA microarray analyses.

RESULTS:

None of the Ptf1a-Cre mice crossbred with Cdh1f/f mice survived for more than 28 days. We observed aberrant epithelial tubules that resembled the structure of acinar-to-ductal metaplasia after postnatal day 6, showing features of pancreatitis. All of the PKC mice died within 10 days. We observed tumorigenicity with increasing stroma-like aggressive tumors. Ptf1a-CreERT models showed that deletion of E-cadherin led to earlier pancreatic intraepithelial neoplasm formation. Cells established from PKC organoids had greater migratory and invasive activities, and these allograft tumors showed a poorly differentiated phenotype. Gene expression analysis indicated that Hdac1 was up-regulated in PKC cell lines and a histone deacetylase 1 inhibitor suppressed PKC cell proliferation.

CONCLUSIONS:

Under physiological conditions, E-cadherin is important for maintaining the tissue homeostasis of the pancreas. Under pathologic conditions with mutational Kras activation, E-cadherin plays an important role in tumor formation via the acquisition of tumorigenic activity.

• Authors: Yoshihiro Kaneta, Takeshi Sato, Yohko Hikiba, Makoto Sugimori, Soichiro Sue, Hiroaki Kaneko, Kuniyasu Irie, Tomohiko Sasaki, Masaaki Kondo, Makoto Chuma, Wataru Shibata, Shin Maeda
• Journal: Cellular and molecular gastroenterology and hepatology (Cell Mol Gastroenterol Hepatol) Vol. 9 Issue 1 Pg. 105-119 ( 2020) ISSN: 2352-345X [Electronic] United States
• PMID: 31526907 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cadherins
• Cdh1 protein, mouse
• Transcription Factors
• transcription factor PTF1
• Hdac1 protein, mouse
• Histone Deacetylase 1
• Hras protein, mouse
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Cadherins (deficiency, genetics)
• Carcinogenesis (genetics, pathology)
• Disease Models, Animal
• Epithelial-Mesenchymal Transition (genetics)
• Gene Expression Regulation, Neoplastic
• Histone Deacetylase 1 (metabolism)
• Humans
• Metaplasia (genetics, pathology)
• Mice
• Mice, Knockout
• Organoids
• Pancreas (pathology)
• Pancreatic Neoplasms (genetics, pathology)
• Pancreatitis (pathology)
• Primary Cell Culture
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• Up-Regulation