Elsevier

Neoplasia

Volume 16, Issue 11, November 2014, Pages 909-917
Neoplasia

Neurogenin 3–Directed Cre Deletion of Tsc1 Gene Causes Pancreatic Acinar Carcinoma1,2

https://doi.org/10.1016/j.neo.2014.08.010Get rights and content
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Abstract

The role of tuberous sclerosis complex (TSC) in the pathogenesis of pancreatic cancers remains largely unknown. The present study shows that neurogenin 3 directed Cre deletion of Tsc1 gene induces the development of pancreatic acinar carcinoma. By cross-breeding the Neurog3-cre mice with Tsc1loxp/loxp mice, we generated the Neurog3-Tsc1−/− transgenic mice in which Tsc1 gene is deleted and mTOR signaling activated in the pancreatic progenitor cells. All Neurog3-Tsc1−/− mice developed notable adenocarcinoma-like lesions in pancreas starting from the age of 100 days old. The tumor lesions are composed of cells with morphological and molecular resemblance to acinar cells. Metastasis of neoplasm to liver and lung was detected in 5% of animals. Inhibition of mTOR signaling by rapamycin significantly attenuated the growth of the neoplasm. Relapse of the neoplasm occurred within 14 days upon cessation of rapamycin treatment. Our studies indicate that activation of mTOR signaling in the pancreatic progenitor cells may trigger the development of acinar carcinoma. Thus, mTOR may serve as a potential target for treatment of pancreatic acinar carcinoma.

Abbreviations

ACC
acinar cell carcinoma
4EBP-1
4E binding protein 1
mTOR
mammlian target of rapamycin
Neurog3
neurogenin 3
PDA
pancreatic ductal adenocarcinoma
S6
ribosomal protein S6
TSC
tuberous sclerosis complex

Cited by (0)

1

Conflict of interest: The authors do not have any disclosure to report.

2

Financial support: None of the above authors have been funded by any National Institutes of Health (NIH) or other applicable grants for this research. The research was funded independently by National Natural Science Foundation of China (81030012, 81330010, 81390354) and American Diabetes Association grant #1-13-BS-225.

3

These authors contributed equally to this work.