Topic Overview:

Most pancreatic ductal adenocarcinoma (PDAC), an almost uniformly lethal disease, is thought to arise from well-defined, noninvasive 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. Tang’s 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. Preliminary studies supporting this application show that conditional genetic ablation of HMGB1 limited to the pancreas (Pdx1-Cre;K-RasG12D/+;HMGB1-/-; termed KCH mice) inhibits autophagy, promotes proliferation, activates normally quiescent pathways, and renders mice extraordinarily sensitive to K-Ras G12D/+-driven pancreatic carcinogenesis. Tang and colleagues found that the progression of PanINs from low-grade PanIN1 to high-grade PanIN3 was observed as early as three to seven days (normally three to nine months) after birth in KCH mice, suggesting a critical role of HMGB1 in the regulation of the earliest events during pancreatic carcinogenesis.