Epithelial Notch signaling is a limiting step for pancreatic carcinogenesis

BMC Cancer

Marsha M Thomas³  Yaqing Zhang³  Esha Mathew¹  Kevin T Kane³  Ivan Maillard²  Marina Pasca di Magliano⁴ 

[1] Cell and Molecular Biology Program, University of Michigan, 2966 Taubman Medical Library, Ann Arbor, MI 48109-0619, USA

[2] Life Science Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA

[3] Department of Surgery, 1500 E Medical Center Drive, Ann Arbor, Michigan 48109-5936, USA

[4] Department of Cell and Developmental Biology, University of Michigan, 3059 A. Alfred Taubman Biomedical Science Research Building, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA

关键词: Genetically engineered mouse model;    Epithelium;    Mastermind-like;    DNMAML;    Notch;    Pancreatic cancer;   

Others  :  1118030
DOI  :  10.1186/1471-2407-14-862

 received in 2014-05-13, accepted in 2014-11-13,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Thomas et al.; licensee BioMed Central Ltd.

【 图 表 】

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