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Epithelial Notch signaling is a limiting step for pancreatic carcinogenesis

BACKGROUND: Pancreatic cancer is one of the deadliest human malignancies, with few therapeutic options. Re-activation of embryonic signaling pathways is commonly in human pancreatic cancer and provided rationale to explore inhibition of these pathways therapeutically. Notch signaling is important du...

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Autores principales: Thomas, Marsha M, Zhang, Yaqing, Mathew, Esha, Kane, Kevin T, Maillard, Ivan, Pasca di Magliano, Marina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289235/
https://www.ncbi.nlm.nih.gov/pubmed/25416148
http://dx.doi.org/10.1186/1471-2407-14-862
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author Thomas, Marsha M
Zhang, Yaqing
Mathew, Esha
Kane, Kevin T
Maillard, Ivan
Pasca di Magliano, Marina
author_facet Thomas, Marsha M
Zhang, Yaqing
Mathew, Esha
Kane, Kevin T
Maillard, Ivan
Pasca di Magliano, Marina
author_sort Thomas, Marsha M
collection PubMed
description BACKGROUND: Pancreatic cancer is one of the deadliest human malignancies, with few therapeutic options. Re-activation of embryonic signaling pathways is commonly in human pancreatic cancer and provided rationale to explore inhibition of these pathways therapeutically. Notch signaling is important during pancreatic development, and it is re-activated in pancreatic cancer. The functional role of Notch signaling during pancreatic carcinogenesis has been previously characterized using both genetic and drug-based approaches. However, contrasting findings were reported based on the study design. In fact, Notch signaling has been proposed to act as tumor-promoter or tumor-suppressor. Given the availability of Notch inhibitors in the clinic, understanding how this signaling pathway contributes to pancreatic carcinogenesis has important therapeutic implications. Here, we interrogated the role of Notch signaling specifically in the epithelial compartment of the pancreas, in the context of a genetically engineered mouse model of pancreatic cancer. METHODS: To inhibit Notch signaling in the pancreas epithelium, we crossed a mouse model of pancreatic cancer based on pancreas-specific expression of mutant Kras with a transgenic mouse that conditionally expresses a dominant negative form of the Mastermind-like 1 gene. MAML is an essential co-activator of the canonical Notch signaling-mediated transcription. DNMAML encodes a truncated MAML protein that represses all canonical Notch mediated transcription in a cell autonomous manner, independent of which Notch receptor is activated. As a result, in mice co-expressing mutant Kras and DNMAML, Notch signaling is inhibited specifically in the epithelium upon Cre-mediated recombination. We explored the effect of epithelial-specific DNMAML expression on Kras-driven carcinogenesis both during normal aging and following the induction of acute pancreatitis. RESULTS: We find that DNMAML expression efficiently inhibits epithelial Notch signaling and delays PanIN formation. However, over time, loss of Notch inhibition allows PanIN formation and progression. CONCLUSIONS: Epithelial-specific Notch signaling is important for PanIN initiation. Our findings indicate that PanIN formation can only occur upon loss of epithelial Notch inhibition, thus supporting an essential role of this signaling pathway during pancreatic carcinogenesis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2407-14-862) contains supplementary material, which is available to authorized users.
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spelling pubmed-42892352015-01-11 Epithelial Notch signaling is a limiting step for pancreatic carcinogenesis Thomas, Marsha M Zhang, Yaqing Mathew, Esha Kane, Kevin T Maillard, Ivan Pasca di Magliano, Marina BMC Cancer Research Article BACKGROUND: Pancreatic cancer is one of the deadliest human malignancies, with few therapeutic options. Re-activation of embryonic signaling pathways is commonly in human pancreatic cancer and provided rationale to explore inhibition of these pathways therapeutically. Notch signaling is important during pancreatic development, and it is re-activated in pancreatic cancer. The functional role of Notch signaling during pancreatic carcinogenesis has been previously characterized using both genetic and drug-based approaches. However, contrasting findings were reported based on the study design. In fact, Notch signaling has been proposed to act as tumor-promoter or tumor-suppressor. Given the availability of Notch inhibitors in the clinic, understanding how this signaling pathway contributes to pancreatic carcinogenesis has important therapeutic implications. Here, we interrogated the role of Notch signaling specifically in the epithelial compartment of the pancreas, in the context of a genetically engineered mouse model of pancreatic cancer. METHODS: To inhibit Notch signaling in the pancreas epithelium, we crossed a mouse model of pancreatic cancer based on pancreas-specific expression of mutant Kras with a transgenic mouse that conditionally expresses a dominant negative form of the Mastermind-like 1 gene. MAML is an essential co-activator of the canonical Notch signaling-mediated transcription. DNMAML encodes a truncated MAML protein that represses all canonical Notch mediated transcription in a cell autonomous manner, independent of which Notch receptor is activated. As a result, in mice co-expressing mutant Kras and DNMAML, Notch signaling is inhibited specifically in the epithelium upon Cre-mediated recombination. We explored the effect of epithelial-specific DNMAML expression on Kras-driven carcinogenesis both during normal aging and following the induction of acute pancreatitis. RESULTS: We find that DNMAML expression efficiently inhibits epithelial Notch signaling and delays PanIN formation. However, over time, loss of Notch inhibition allows PanIN formation and progression. CONCLUSIONS: Epithelial-specific Notch signaling is important for PanIN initiation. Our findings indicate that PanIN formation can only occur upon loss of epithelial Notch inhibition, thus supporting an essential role of this signaling pathway during pancreatic carcinogenesis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2407-14-862) contains supplementary material, which is available to authorized users. BioMed Central 2014-11-22 /pmc/articles/PMC4289235/ /pubmed/25416148 http://dx.doi.org/10.1186/1471-2407-14-862 Text en © Thomas et al.; licensee BioMed Central Ltd. 2014 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Thomas, Marsha M
Zhang, Yaqing
Mathew, Esha
Kane, Kevin T
Maillard, Ivan
Pasca di Magliano, Marina
Epithelial Notch signaling is a limiting step for pancreatic carcinogenesis
title Epithelial Notch signaling is a limiting step for pancreatic carcinogenesis
title_full Epithelial Notch signaling is a limiting step for pancreatic carcinogenesis
title_fullStr Epithelial Notch signaling is a limiting step for pancreatic carcinogenesis
title_full_unstemmed Epithelial Notch signaling is a limiting step for pancreatic carcinogenesis
title_short Epithelial Notch signaling is a limiting step for pancreatic carcinogenesis
title_sort epithelial notch signaling is a limiting step for pancreatic carcinogenesis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289235/
https://www.ncbi.nlm.nih.gov/pubmed/25416148
http://dx.doi.org/10.1186/1471-2407-14-862
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