Pancreatitis-Induced p62 Accumulation Promotes Pancreatic Cancer

Most pancreatic intraepithelial neoplasia 1 (PanIN1) lesions, which frequently occur in patients with chronic pancreatitis and harbor oncogenic KRAS, rarely progress to pancreatic ductal adenocarcinoma (PDAC) even though oncogenic KRAS is a known driver of PDAC. Defective autophagic–lysosomal degradation, which is driven by IKKα loss and results in the accumulation of autophagy substrates such as p62, in acinar cells is a common feature of risk factors associated with the progression of PanIN1 lesions to PDAC. To elucidate the mechanisms underlying the progression of PanIN lesions to PDAC, Todoric and colleagues investigated the role of p62 in PDAC. p62 accumulation was demonstrated in human PanIN1 lesions and PDAC and corresponded with increased expression of NRF2 target genes, which is activated by p62, and MDM2. p62 ablation resulted in the loss of stemness markers and MDM2 in human PDAC cell lines, and ablation of either p62 or NRF2 resulted in loss of human PDAC cell line stemness. Further, IKKα loss resulted in increased growth of human PDAC cell line xenografts and stemness, and mouse models of chronic pancreatitis expressing Kras^G12D exhibited increased acinar-to-ductal metaplasia (ADM), accelerated PanIN1 formation, and increased p62 accumulation compared to noninflamed mice expressing Kras^G12D. In vivo p62 depletion resulted in NRF2 loss, and in vivo depletion of p62 or NRF2 inhibited ADM and the formation of advanced PanIN lesions, decreased the expression of stemness genes and MDM2, and prolonged survival. Expression of the intracellular domain of Notch1, which promotes PanIN formation in the presence of Kras^G12D, rescued NRF2 loss in vitro and p62 loss in vivo. Mechanistically, NRF2 regulates MDM2 transcription to upregulate the expression of Notch target genes and stem cell markers and inhibits p53 activation and senescence. These findings elucidate a mechanism by which p62 promotes PDAC tumorigenesis and suggest that treatment with MDM2 inhibitors may be inhibit the progression of PanIN lesions to PDAC.

Todoric J, Antonucci L, Di Caro G, Li N, Wu X, Lytle NK, et al. Stress-activated NRF2-MDM2 cascade controls neoplastic progression in pancreas. Cancer Cell 2017 Nov 16 [Epub ahead of print].

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