Overexpression of HER2 in the pancreas promotes development of intraductal papillary mucinous neoplasms in mice

Wataru Shibata,Hideaki Ijichi,Ryutaro Mori,Takeshi Sato,Kosuke Sakitani,Shin Maeda,Yasuaki Ishii,Yohko Hikiba,Nobumi Suzuki,Itaru Endo,Makoto Sugimori,Hiroto Kinoshita,Soichiro Sue

doi:10.1038/s41598-018-24375-2

Abstract

Pancreatic ductal adenocarcinoma (PDA) has a 5-year survival rate of less than 5% and is the sixth leading cause of cancer death. Although KRAS mutations are one of the major driver mutations in PDA, KRAS mutation alone is not sufficient to induce invasive pancreatic cancer in mice model. HER2, also known as ERBB2, is a receptor tyrosine kinase, and overexpression of HER2 is associated with poor clinical outcomes in pancreatic cancer. However, no report has shown whether HER2 and its downstream signaling contributes to the pancreatic cancer development. By immunohistochemical analysis in human cases, HER2 protein expression was detected in 40% of PDAs and 29% of intraductal papillary mucinous carcinomas, another type of pancreatic cancer. In a mouse model, we showed overexpression of activated HER2 (HER2NT) in the pancreas, in which cystic neoplastic lesions resembling intraductal papillary mucinous neoplasm-like lesions in humans had developed. We also found that HER2NT cooperated with oncogenic Kras to accelerate the development of pancreatic intraepithelial neoplasms. In addition, using pancreatic organoids in 3D cultures, we found that organoids cultured from HER2NT/Kras double transgenic mice showed proliferative potential and tumorigenic ability cooperatively. HER2-signaling inhibition was suggested to be an new therapeutic target in some types of PDAs.

Highlights

Pancreatic ductal adenocarcinoma (PDA) has a 5-year survival rate of less than 5% and is the sixth leading cause of cancer death[1]
We showed that pancreas-specific overexpression of activated Human epidermal growth factor-2 (HER2) in mice led to intraductal papillary mucinous neoplasm (IPMN)-like lesions
We assessed a role of activated HER2 in Kras-driven pancreatic neoplasms, by using mice harboring activated HER2 and/or Kras mutation in pancreas[11], and found that a cooperative role between activated HER2 and oncogenic Kras accelerated the development of pancreatic intraepithelial neoplasms

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDA) has a 5-year survival rate of less than 5% and is the sixth leading cause of cancer death[1]. KRAS mutations are one of the major driver mutations in PDA, KRAS mutation alone is not sufficient to induce invasive pancreatic cancer in mice model[2,3,4,5]. No study has been shown how HER2 alone or with Kras mutation is involved in the development of pancreatic neoplasms in genetically engineered mouse models. We showed that pancreas-specific overexpression of activated HER2 in mice led to intraductal papillary mucinous neoplasm (IPMN)-like lesions. Immunohistochemical staining of HER2 in PDA (tissue array) or surgically resected IPMC (original magnification 100×). Non-invasive Minimally invasive Invasive Head Body Tail Head, body and tail Main duct Branch duct Mixed

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Conclusion