MYC Instructs and Maintains Pancreatic Adenocarcinoma Phenotype

• Published in: Cancer discovery Vol. 10; no. 4; pp. 588 - 607
• Main Authors: Sodir, Nicole M., Kortlever, Roderik M., Barthet, Valentin J.A., Campos, Tania, Pellegrinet, Luca, Kupczak, Steven, Anastasiou, Panayiotis, Swigart, Lamorna Brown, Soucek, Laura, Arends, Mark J., Littlewood, Trevor D., Evan, Gerard I.
• Format: Journal Article
• Language: English
• Published: United States 01.04.2020
• Subjects: Animals; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - pathology; Genes, myc; Humans; Mice; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Phenotype; Prognosis; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins p21(ras) - genetics
• ISSN: 2159-8274; 2159-8290; 2159-8290
• DOI: 10.1158/2159-8290.CD-19-0435

The signature features of pancreatic ductal adenocarcinoma (PDAC) are its fibroinflammatory stroma, poor immune activity, and dismal prognosis. We show that acute activation of in indolent pancreatic intraepithelial neoplasm (PanIN) epithelial cells is, alone, sufficient to trigger immediate release of instructive signals that together coordinate changes in multiple stromal and immune-cell types and drive transition to pancreatic adenocarcinomas that share all the characteristic stromal features of their spontaneous human counterpart. We also demonstrate that this -driven PDAC switch is completely and immediately reversible: deactivation/inhibition triggers meticulous disassembly of advanced PDAC tumor and stroma and concomitant death of tumor cells. Hence, both the formation and deconstruction of the complex PDAC phenotype are continuously dependent on a single, reversible switch. SIGNIFICANCE: We show that activation in indolent -induced PanIN epithelium acts as an immediate pleiotropic switch, triggering tissue-specific signals that instruct all the diverse signature stromal features of spontaneous human PDAC. Subsequent deactivation or inhibition immediately triggers a program that coordinately disassembles PDAC back to PanIN. .