Identification of Sox9-Dependent Acinar-to-Ductal Reprogramming as the Principal Mechanism for Initiation of Pancreatic Ductal Adenocarcinoma

SummaryTumors are largely classified by histologic appearance, yet morphologic features do not necessarily predict cellular origin. To determine the origin of pancreatic ductal adenocarcinoma (PDA), we labeled and traced pancreatic cell populations after induction of a PDA-initiating Kras mutation. Our studies reveal that ductal and stem-like centroacinar cells are surprisingly refractory to oncogenic transformation, whereas acinar cells readily form PDA precursor lesions with ductal features. We show that formation of acinar-derived premalignant lesions depends on ectopic induction of the ductal gene Sox9. Moreover, when concomitantly expressed with oncogenic Kras, Sox9 accelerates formation of premalignant lesions. These results provide insight into the cellular origin of PDA and suggest that its precursors arise via induction of a duct-like state in acinar cells.

Graphical AbstractFigure optionsDownload high-quality image (194 K)Download as PowerPoint slideHighlights
► Preneoplastic lesions rarely arise from pancreatic ductal/centroacinar cells
► Acinar cells are the predominant cells of origin for pancreatic preneoplastic lesions
► Initiation of pancreatic cancer depends on acinar induction of the ductal gene Sox9
► Sox9 synergizes with KrasG12D and injury in acinar-to-ductal cell reprogramming