| First Author | Todoric J | Year | 2017 |
| Journal | Cancer Cell | Volume | 32 |
| Issue | 6 | Pages | 824-839.e8 |
| PubMed ID | 29153842 | Mgi Jnum | J:252273 |
| Mgi Id | MGI:6103652 | Doi | 10.1016/j.ccell.2017.10.011 |
| Citation | Todoric J, et al. (2017) Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas. Cancer Cell 32(6):824-839.e8 |
| abstractText | 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. |
