Abstract B070: Deletion of NEMO inhibits PanIN development but accelerates PanIN progression towards PDAC

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest types of cancer with a 5-year survival rate of less than 10%. Importantly, the canonical NF-κB pathway, which regulates critical cellular functions including inflammation, is active in the majority of PDAC cases as well as in pancreatic intraepithelial neoplasias (PanINs). Our study investigated the role of NF-κB signaling in the development and progression of PanINs and PDAC by deleting NF-κB essential modulator (NEMO), an essential protein for the activation of the NF-κB pathway. We used genetically-modified mice with pancreas-specific expression of oncogenic KRAS (KC mouse model). To blunt the canonical NF-κB pathway, KC mice were crossed to NEMO-floxed mice, allowing pancreas-specific deletion of NEMO (KNeC mouse model). The mice were injected with cerulein to promote the development of pancreatitis and accelerate the development of PDAC. Analysis of the pancreata at the time point of 8 weeks revealed that NEMO deletion reduced the infiltration of immune cells and the collagen deposition in the pancreas. However, no significant difference in the number of PanINs between the KC and KNeC mice was observed. In contrast, analysis at the time point of 10 months demonstrated that NEMO deletion drastically reduced the total number of PanINs and the field covered by desmoplasia. In addition, KNeC pancreata exhibited reduced inflammation compared to KC pancreata. Strikingly, however, NEMO deletion accelerated the progression of low-grade to high-grade PanINs and eventually to PDAC and reduced the lifespan of the mice. Mechanistically, NEMO deletion blocked the oncogene-induced senescence (OIS) that is active in low-grade PanINs. RNA-seq analysis revealed that inhibition of OIS resulted in reduced expression of the senescence-associated secretory phenotype (SASP). Finally, NEMO deletion increased the proliferation rate and the accumulation of DNA damage in precancerous lesion cells, supporting their progression to high-grade PanINs. Collectively, our study gives a mechanistic insight of the role of NF-κB in the development and progression of precancerous lesions. It underscores that NEMO exerts oncogene properties by supporting the development of new low-grade PanINs, but at the same time, it exerts tumor-suppressor properties by maintaining OIS in PanINs. Citation Format: Miltiadis Tsesmelis, Melanie Gerstenlauer, Uta Manfras, Thomas F.E. Barth, Harald Jakob Maier, Lap Kwan Chan, Thomas Wirth. Deletion of NEMO inhibits PanIN development but accelerates PanIN progression towards PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B070.