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

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40 Citations (Scopus)

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 KrasG12D 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. Todoric et al. demonstrate that pancreatitis-induced accumulation of the autophagy substrate p62/SQSTM1 in the context of oncogenic KRAS promotes progression to pancreatic ductal adenocarcinoma. This p62 function relies on NRF2-driven induction of MDM2 and both p53 dependent and independent activity of MDM2.

Original languageEnglish
Pages (from-to)824-839.e8
JournalCancer Cell
Volume32
Issue number6
Early online date16 Nov 2017
DOIs
Publication statusPublished - 11 Dec 2017

Keywords

  • acinar cell reprogramming
  • IKKα
  • impaired autophagy
  • MDM2
  • NRF2
  • p62
  • pancreatic ductal adenocarcinoma

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    Todoric, J., Antonucci, L., Di Caro, G., Li, N., Wu, X., Lytle, N. K., Dhar, D., Banerjee, S., Fagman, J. B., Browne, C. D., Umemura, A., Valasek, M. A., Kessler, H., Tarin, D., Goggins, M., Reya, T., Diaz-Meco, M., Moscat, J., & Karin, M. (2017). Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas. Cancer Cell, 32(6), 824-839.e8. https://doi.org/10.1016/j.ccell.2017.10.011