Most pancreatic ductal adenocarcinoma (PDAC), an almost uniformly lethal disease, is thought to arise from well-defined, non-invasive precursor lesions, termed pancreatic ductal intraepithelial neoplastic lesions (PanINs). Studies of human pancreatic carcinogenesis have been greatly facilitated by the development of a genetically engineered mouse model that expresses oncogenic K-Ras under a pancreatic promoter Pdx1-Cre:KrasG12D/+. A more detailed understanding of how this pathway accelerates pancreatic carcinogenesis may allow improved early detection, prevention, and therapeutic strategies. Our recent studies demonstrate that high mobility group box 1 (HMGB1) is a critical regulator of autophagy, a major pathway for degradation of effete proteins and damaged organelles. We found that conditional genetic ablation of HMGB1 limited to the pancreas (Pdx1-Cre;K-Ras G12D/+;HMGB1-/-; termed KCH mice) inhibits autophagy, promotes proliferation, activates normally quiescent pathways, and renders mice extraordinarily sensitive to K-RasG12D/+-driven pancreatic carcinogenesis. We found that the progression of PanINs from low grade PanIN1 to high grade PanIN3 was observed as early as three-seven days (normally three-nine months) after birth in KCH mice, suggesting a critical role of HMGB1 in regulation of the earliest events during pancreatic carcinogenesis. This extraordinarily rapid murine pancreatic cancer model that we have created will allow us to dissect the mechanism by which loss of HMGB1 contributes to the process.

Citation Format: Rui Kang, Qiuhong Zhang, Wen Hou, Ruochan Chen, Michael Lotze, Herbert Zeh, Daolin Tang. HMGB1 regulates pancreatic cancer initiation and pogression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2031. doi:10.1158/1538-7445.AM2014-2031