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

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

Rolle der Autophagie in Erkrankungen der Bauchspeicheldrüse

To analyze the role of autophagy in the pancreas, mice with pancreas-specific, genetic deletion of Atg5 (A5) were characterized. Moreover, mice were treated with specific diets to study the effect of dietary composition on phenotype development. A5 mice developed atrophic, chronic pancreatitis (CP) in a gender and nutrition dependent fashion. Importantly, similarities with pancreata from human CP patients reveal A5 mice as the first genetic mouse model of human CP.Zur Untersuchung der Autophagie im Pankreas wurden Mäuse mit pankreasspezifischer, genetischer Inaktivierung von Atg5 (A5) charakterisiert. Behandlungen mit spezifischen Diäten wurden vollzogen, um den Effekt von Diätkompositionen auf die Phänotypentwicklung zu studieren. A5 Mäuse entwickelten atrophe, chronische Pankreatitis (CP) abhängig von Geschlecht und Diät. Ähnlichkeiten mit humaner CP unterstreichen desweiteren die Bedeutung von A5 Mäusen als erstes genetisches Mausmodell humaner CP