Title | Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | 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 |
Journal | Cancer Cell |
Volume | 32 |
Issue | 6 |
Pagination | 824-839.e8 |
Date Published | 2017 Dec 11 |
ISSN | 1878-3686 |
Keywords | 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 |
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 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. |
DOI | 10.1016/j.ccell.2017.10.011 |
Alternate Journal | Cancer Cell |
PubMed ID | 29153842 |
PubMed Central ID | PMC5730340 |
Grant List | R01 CA155620 / CA / NCI NIH HHS / United States P01 DK098108 / DK / NIDDK NIH HHS / United States R01 CA172025 / CA / NCI NIH HHS / United States R01 CA211794 / CA / NCI NIH HHS / United States R01 CA186043 / CA / NCI NIH HHS / United States R01 CA132847 / CA / NCI NIH HHS / United States R01 CA134530 / CA / NCI NIH HHS / United States R35 CA197699 / CA / NCI NIH HHS / United States R01 CA192642 / CA / NCI NIH HHS / United States R01 CA218254 / CA / NCI NIH HHS / United States R01 CA163798 / CA / NCI NIH HHS / United States R03 CA167120 / CA / NCI NIH HHS / United States F31 CA206416 / CA / NCI NIH HHS / United States |
Related Lab:
Related Faculty:
Jorge Moscat, Ph.D. Maria Diaz-Meco Conde, Ph.D.