MYC Instructs and Maintains Pancreatic Adenocarcinoma Phenotype
- 1 April 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 10 (4), 588-607
- https://doi.org/10.1158/2159-8290.cd-19-0435
Abstract
The signature features of pancreatic ductal adenocarcinoma (PDAC) are its fibroinflammatory stroma, poor immune activity and dismal prognosis. We show that acute activation of Myc in indolent PanIN epithelial cells in vivo is, alone, sufficient to trigger immediate release of instructive signals that together coordinate changes in multiple stromal and immune cell types and trigger transition to pancreatic adenocarcinomas that share all the characteristic stromal features of their spontaneous human counterpart. We also demonstrate that this Myc-driven PDAC switch is completely and immediately reversible: Myc 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 Myc switch.Keywords
Other Versions
Funding Information
- Cancer Research UK (C4750/A12077, C4750/A19013A)
- European Research Council (294851)
- Stand Up To Cancer (SU2C-AACRDT20-16)
This publication has 121 references indexed in Scilit:
- Identification of Axl as a downstream effector of TGF-β1 during Langerhans cell differentiation and epidermal homeostasisThe Journal of Experimental Medicine, 2012
- Enzymatic Targeting of the Stroma Ablates Physical Barriers to Treatment of Pancreatic Ductal AdenocarcinomaCancer Cell, 2012
- Tumor-infiltrating neutrophils in pancreatic neoplasiaLaboratory Investigation, 2011
- Analysis of the Human Pancreatic Stellate Cell Secreted ProteomePancreas, 2011
- Overexpression of CXCL5 Is Associated With Poor Survival in Patients With Pancreatic CancerThe American Journal of Pathology, 2011
- Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinomaProceedings of the National Academy of Sciences of the United States of America, 2010
- Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instabilityCarcinogenesis: Integrative Cancer Research, 2009
- Distinct Thresholds Govern Myc's Biological Output In VivoCancer Cell, 2008
- Stabilization of β-Catenin Induces Pancreas Tumor FormationGastroenterology, 2008
- Both p16 Ink4a and the p19 Arf -p53 pathway constrain progression of pancreatic adenocarcinoma in the mouseProceedings of the National Academy of Sciences of the United States of America, 2006