Cross-talk between IKK2 and Notch promotes pancreatic cancer progression in mice through Hes1 mediated PPAR gamma inhibition

E. Maniati, M. Bossard, N. Cook, J. Candido, N. Emami-Shahri, S. Nedospasov, F. Balkwill, D. Tuveson, T. Hagemann

Research output: Contribution to journalMeeting Abstractpeer-review


Activating mutations of Kras are found in more than 90% of pancreatic ductal adenocarcinomas (PDAC) and can result in increasedactivity of the NF-jB pathway, leading to a constitutive production ofpro-inflammatory cytokines, such as TNF-a. Well-described mousemodels with pancreas-specific activation of oncogenic Kras display thefull spectrum of pancreatic intraepithelial neoplasias (PanINs) andrecapitulate the major features of human PDAC. We used the kras +/LSL-G12D; pdx1-cre model to determine the role of IKK2/NF-jB signalling in formation and progression of PanINs. We showed that genetic deletion of ikk2 in kras+/LSL-G12D; ikk2f/f; pdx1-cre mice blockedthe progression of PanIN lesions. We further demonstrated that TNF-astimulation of initiated epithelial cells via IKK2 engaged with canonicalNotch signalling to upregulate the expression of primary Notch targetgenes. The cross-talk between NF-jB and Notch downregulated pparg,a repressor of inflammatory gene expression and retained a constitutive production of pro-inflammatory mediators and cytokines bythe transformed cells. Our findings reveal a malignant cell-autonomous, low-grade inflammatory process operating from the very earlystages of Kras-driven pancreatic carcinogenesis which acts as a tumourpromoter for PanIN lesions through Hes1 mediated inhibition ofPPARc.
Original languageEnglish
Article number634
Pages (from-to)169-169
Number of pages1
Issue numberSuppl. 1
Publication statusPublished - Dec 2011

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


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