1. Stressing Out PanIN: NRF2 Pushes over the Edge
Laura Torrente, Gina M. DeNicola 
Cancer Cell 
Volume 32, Issue 6, Pages (December 2017)
DOI: /j.ccell
Copyright © 2017 Elsevier Inc. Terms and Conditions

2. Figure 1
Schematic Representation of Adaptive Cellular Mechanisms that Occur during the Stages Prior the Development of PDAC (Top) and the Respective Histological Alterations Observed in the Exocrine Pancreas (Bottom)
Left: in normal tissues from healthy individuals, KEAP1 constitutively targets NRF2 for degradation, impeding newly synthetized NRF2 from reaching the nucleus to activate the transcription of its target genes. At the tissue level, acinar cells organize as clusters that share a central lumen, while ductal cells construct the epithelial lining of the tubes that traverses the pancreas to the duodenum. Middle: oncogenic activation of KRAS drives transdifferentiation of acinar cells to duct-like cells in a process known as acinar-to-ductal metaplasia (ADM), followed by progressive dysplasia that leads to the formation of premalignant lesions (PanIN). These changes are translated into the progressive loss of acinar cells and their replacement by highly proliferative ductal cells that harbor multiple somatic mutations. Sustained activation of KRAS increases the levels and activity of NRF2, which participates in the maintenance and progression of premalignant lesions. Right: additional cellular stresses that promote chronic inflammation alter autophagy flux, thereby triggering the accumulation of p62 and subsequent KEAP1 sequestration. Consequently, NRF2 evades proteasomal degradation and activates the transcription of MDM2, which in turn mediates p53 degradation and activates the Notch signaling pathway. p53 degradation thereby allows PanIN progression and PDAC formation by preventing the onset of senescence. Thus, KRAS mutation and defective autophagy co-operate to activate the NRF2 cascade, thereby promoting malignant transformation.
Cancer Cell  , DOI: ( /j.ccell )
Copyright © 2017 Elsevier Inc. Terms and Conditions