期刊
CANCER CELL
卷 32, 期 6, 页码 824-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2017.10.011
关键词
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资金
- Austrian Science Fund Erwin Schroedinger Fellowship [J3233]
- Univ. Prof. Dr. Matthias M. Muller Fellowship
- OOGLMKC
- Austrian Program for Advanced Research and Technology of the Austrian Academy of Sciences
- Associazione Italiana per la Ricerca sul Cancro (AIRC) Fellowship
- European Union
- AIRC Fellowship [16230]
- Marie Curie Actions European Union
- Susan G. Komen for the Cure [KG111506]
- Swedish Research Council [524-2011-6817]
- Swedish Society for Medical Research
- CureSearch Young Investigator Award
- American Liver Foundation Liver Scholar Award
- NIH Minority Supplement [R01AI043477]
- Rotary Foundation Global Grant Scholarship [25480]
- NIH [GM007752, CA206416, CA62924, CA197699, CA163798, CA167120, CA186043, CA211794, CA132847, CA172025, CA134530, CA030199, CA192642]
- DOD [W81XWH-13-1-0354, W81XWH-13-1-0353]
- Stand Up To Cancer-Cancer Research UK-Lustgarten Foundation Pancreatic Cancer Dream Team Research Grant [SU2C-AACR-DT-20-16]
- Lustgarten Foundation [RFP-B-007]
- Austrian Science Fund (FWF) [J3233] Funding Source: Austrian Science Fund (FWF)
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.
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