title: RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis.
abstract: 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.
authors.forename: Marina
authors.initials: M
authors.lastname: Lesina
authors.forename: Sonja Maria
authors.initials: SM
authors.lastname: Wörmann
authors.forename: Jennifer
authors.initials: J
authors.lastname: Morton
authors.forename: Kalliope Nina
authors.initials: KN
authors.lastname: Diakopoulos
authors.forename: Olga
authors.initials: O
authors.lastname: Korneeva
authors.forename: Margit
authors.initials: M
authors.lastname: Wimmer
authors.forename: Henrik
authors.initials: H
authors.lastname: Einwächter
authors.forename: Jan
authors.initials: J
authors.lastname: Sperveslage
authors.forename: Ihsan Ekin
authors.initials: IE
authors.lastname: Demir
authors.forename: Timo
authors.initials: T
authors.lastname: Kehl
authors.forename: Dieter
authors.initials: D
authors.lastname: Saur
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwälder
authors.forename: Jörg Manfred
authors.initials: JM
authors.lastname: Steiner
authors.forename: Timothy Cragin
authors.initials: TC
authors.lastname: Wang
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: Roland Michael
authors.initials: RM
authors.lastname: Schmid
authors.forename: Hana
authors.initials: H
authors.lastname: Algül
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism*; D016922:Cellular Senescence; D054360:Chemokine CXCL1 / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D012333:RNA, Messenger; D023063:Receptors, Interleukin-8B; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D018631:ras Proteins