Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas

Jelena Todoric; Laura Antonucci; Giuseppe Di Caro; Ning Li; Xuefeng Wu; Nikki K Lytle; Debanjan Dhar; Sourav Banerjee; Johan B Fagman; Cecille D Browne; Atsushi Umemura; Mark A Valasek; Hannes Kessler; David Tarin; Michael Goggins; Tannishtha Reya; Maria Diaz-Meco; Jorge Moscat; Michael Karin

doi:10.1016/j.ccell.2017.10.011

Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas

Cancer Cell. 2017 Dec 11;32(6):824-839.e8. doi: 10.1016/j.ccell.2017.10.011. Epub 2017 Nov 16.

Authors

Jelena Todoric¹, Laura Antonucci², Giuseppe Di Caro², Ning Li², Xuefeng Wu², Nikki K Lytle³, Debanjan Dhar², Sourav Banerjee⁴, Johan B Fagman², Cecille D Browne², Atsushi Umemura⁵, Mark A Valasek⁶, Hannes Kessler², David Tarin⁶, Michael Goggins⁷, Tannishtha Reya³, Maria Diaz-Meco⁸, Jorge Moscat⁸, Michael Karin⁹

Affiliations

¹ Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
² Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
³ Departments of Pharmacology and Medicine, Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
⁴ Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
⁵ Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 602-8566 Kyoto, Japan.
⁶ Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
⁷ Departments of Medicine (Gastroenterology) and Radiology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
⁸ Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
⁹ Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: [email protected].

Abstract

Despite expression of oncogenic KRAS, premalignant pancreatic intraepithelial neoplasia 1 (PanIN1) lesions rarely become fully malignant pancreatic ductal adenocarcinoma (PDAC). The molecular mechanisms through which established risk factors, such as chronic pancreatitis, acinar cell damage, and/or defective autophagy increase the likelihood of PDAC development are poorly understood. We show that accumulation of the autophagy substrate p62/SQSTM1 in stressed Kras^G12D acinar cells is associated with PDAC development and maintenance of malignancy in human cells and mice. p62 accumulation promotes neoplastic progression by controlling the NRF2-mediated induction of MDM2, which acts through p53-dependent and -independent mechanisms to abrogate checkpoints that prevent conversion of differentiated acinar cells to proliferative ductal progenitors. MDM2 targeting may be useful for preventing PDAC development in high-risk individuals.

Keywords: IKKα; MDM2; NRF2; acinar cell reprogramming; impaired autophagy; p62; pancreatic ductal adenocarcinoma.

MeSH terms

Acinar Cells / metabolism
Acinar Cells / pathology
Adenocarcinoma in Situ / metabolism
Adenocarcinoma in Situ / pathology*
Animals
Carcinoma, Pancreatic Ductal / metabolism
Carcinoma, Pancreatic Ductal / pathology*
Disease Progression
Heterografts
Humans
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, SCID
NF-E2-Related Factor 2 / metabolism*
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology*
Proto-Oncogene Proteins c-mdm2 / metabolism*
Signal Transduction / physiology

Substances

NF-E2-Related Factor 2
NFE2L2 protein, human
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2

Abstract

MeSH terms

Substances

Grants and funding