Acinar Cell Transdifferentiation Sets The Stage For Early Tumor Heterogeneity

Prior to PanIN formation, acinar cells harboring oncogenic Kras gradually lose their acinar character and take on a ductal phenotype in a process known as acinar-to-ductal metaplasia. Rather than mimicking a normal pancreatic duct, metaplastic ducts take on a proliferative biliary progenitor phenotype, marked by the expression of SOX17 and PDX1 and the presence of numerous tuft cells, recently identified as a PanIN initiating cells. Manipulation of SOX17 and PDX1 in vivo reveal them to be a transdifferentiation promoter and suppressor, respectively, both greatly affecting tuft cell genesis and tumor formation. These opposing roles of developmental transcription factors during tumorigenesis implicate the usurpation of a differentiation program that significantly contributes to cellular heterogeneity within early pre-cancerous lesions of the pancreas. Citation Format: Kenneth K. Takeuchi, Kathleen E. Delgiorno, Christopher J. Halbrook, Howard C. Crawford. Acinar cell transdifferentiation sets the stage for early tumor heterogeneity. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA13.