Faculty Collaboration Database

Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas. Cancer Cell 2017 Dec 11;32(6):824-839.e8

Date

11/21/2017

Pubmed ID

29153842

Pubmed Central ID

PMC5730340

DOI

10.1016/j.ccell.2017.10.011

Scopus ID

2-s2.0-85034422866 (requires institutional sign-in at Scopus site)   96 Citations

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.

Author List

Todoric J, Antonucci L, Di Caro G, Li N, Wu X, Lytle NK, Dhar D, Banerjee S, Fagman JB, Browne CD, Umemura A, Valasek MA, Kessler H, Tarin D, Goggins M, Reya T, Diaz-Meco M, Moscat J, Karin M

Author

Nikki K. Lytle PhD Assistant Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

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