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Lesina, M.* ; Wörmann, S.M.* ; Morton, J.* ; Diakopoulos, K.N.* ; Korneeva, O.* ; Wimmer, M.* ; Einwächter, H.* ; Sperveslage, J.* ; Demir, I.E.* ; Kehl, T.* ; Saur, D.* ; Sipos, B.* ; Heikenwälder, M. ; Steiner, J.M.* ; Wang, T.C.* ; Sansom, O.J.* ; Schmid, R.M.* ; Algül, H.*

RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis.

J. Clin. Invest. 126, 2919-2932 (2016)
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Tumor suppression that is mediated by oncogene-induced senescence (OIS) is considered to function as a safeguard during development of pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that regulate OIS in PDAC are poorly understood. Here, we have determined that nuclear RelA reinforces OIS to inhibit carcinogenesis in the Kras mouse model of PDAC. Inactivation of RelA accelerated pancreatic lesion formation in Kras mice by abrogating the senescence-associated secretory phenotype (SASP) gene transcription signature. Using genetic and pharmacological tools, we determined that RelA activation promotes OIS via elevation of the SASP factor CXCL1 (also known as KC), which activates CXCR2, during pancreatic carcinogenesis. In Kras mice, pancreas-specific inactivation of CXCR2 prevented OIS and was correlated with increased tumor proliferation and decreased survival. Moreover, reductions in CXCR2 levels were associated with advanced neoplastic lesions in tissue from human pancreatic specimens. Genetically disabling OIS in Kras mice caused RelA to promote tumor proliferation, suggesting a dual role for RelA signaling in pancreatic carcinogenesis. Taken together, our data suggest a pivotal role for RelA in regulating OIS in preneoplastic lesions and implicate the RelA/CXCL1/CXCR2 axis as an essential mechanism of tumor surveillance in PDAC.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Nf-kappa-b; Cellular Senescence; Ductal Adenocarcinoma; Secretory Phenotype; Suppressor-cells; Mouse Model; Macrophage Plasticity; Cancer Development; Tumor Suppression; Nemo/ikk-gamma
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Journal Journal of Clinical Investigation
Quellenangaben Volume: 126, Issue: 8, Pages: 2919-2932 Article Number: , Supplement: ,
Publisher American Society of Clinical Investigation
Publishing Place Ann Arbor
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Virology (VIRO)