학술논문
NEMO/NF-κB signaling functions as a double-edged sword in PanIN formation versus progression to pancreatic cancer.
Document Type
Academic Journal
Author
Tsesmelis M; Institute of Physiological Chemistry, University of Ulm, Meyerhofstrasse, 89081, Ulm, Baden-Württemberg, Germany.; Büttner UFG; Institute of Physiological Chemistry, University of Ulm, Meyerhofstrasse, 89081, Ulm, Baden-Württemberg, Germany.; Gerstenlauer M; Institute of Physiological Chemistry, University of Ulm, Meyerhofstrasse, 89081, Ulm, Baden-Württemberg, Germany.; Manfras U; Institute of Physiological Chemistry, University of Ulm, Meyerhofstrasse, 89081, Ulm, Baden-Württemberg, Germany.; Tsesmelis K; Institute of Physiological Chemistry, University of Ulm, Meyerhofstrasse, 89081, Ulm, Baden-Württemberg, Germany.; Du Z; Institute of Physiological Chemistry, University of Ulm, Meyerhofstrasse, 89081, Ulm, Baden-Württemberg, Germany.; Sperb N; Institute of Physiological Chemistry, University of Ulm, Meyerhofstrasse, 89081, Ulm, Baden-Württemberg, Germany.; Weissinger SE; Alb Fils Kliniken Göppingen, 73035, Göppingen, Baden-Württemberg, Germany.; Möller P; Institute of Pathology, University of Ulm, 89081, Ulm, Baden-Württemberg, Germany.; Barth TFE; Institute of Pathology, University of Ulm, 89081, Ulm, Baden-Württemberg, Germany.; Maier HJ; Institute of Physiological Chemistry, University of Ulm, Meyerhofstrasse, 89081, Ulm, Baden-Württemberg, Germany.; Novartis Pharma, 4056, Basel, AG, Switzerland.; Chan LK; Institute of Physiological Chemistry, University of Ulm, Meyerhofstrasse, 89081, Ulm, Baden-Württemberg, Germany. lapkwan.chan@usz.ch.; Department of Pathology and Molecular Pathology, University Hospital of Zurich, 8091, Zurich, Switzerland. lapkwan.chan@usz.ch.; Institute of Molecular Cancer Research, University of Zurich, 8057, Zurich, Switzerland. lapkwan.chan@usz.ch.; Wirth T; Institute of Physiological Chemistry, University of Ulm, Meyerhofstrasse, 89081, Ulm, Baden-Württemberg, Germany. thomas.wirth@uni-ulm.de.
Source
Publisher: BioMed Central Country of Publication: England NLM ID: 101147698 Publication Model: Electronic Cited Medium: Internet ISSN: 1476-4598 (Electronic) Linking ISSN: 14764598 NLM ISO Abbreviation: Mol Cancer Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is marked by a dismal survival rate, lacking effective therapeutics due to its aggressive growth, late-stage diagnosis, and chemotherapy resistance. Despite debates on NF-κB targeting for PDAC treatment, no successful approach has emerged.
Methods: To elucidate the role of NF-κB, we ablated NF-κB essential modulator (NEMO), critical for conventional NF-κB signaling, in the pancreata of mice that develop precancerous lesions (KC mouse model). Secretagogue-induced pancreatitis by cerulein injections was utilized to promote inflammation and accelerate PDAC development.
Results: NEMO deletion reduced fibrosis and inflammation in young KC mice, resulting in fewer pancreatic intraepithelial neoplasias (PanINs) at later stages. Paradoxically, however, NEMO deletion accelerated the progression of these fewer PanINs to PDAC and reduced median lifespan. Further, analysis of tissue microarrays from human PDAC sections highlighted the correlation between reduced NEMO expression in neoplastic cells and poorer prognosis, supporting our observation in mice. Mechanistically, NEMO deletion impeded oncogene-induced senescence (OIS), which is normally active in low-grade PanINs. This blockage resulted in fewer senescence-associated secretory phenotype (SASP) factors, reducing inflammation. However, blocked OIS fostered replication stress and DNA damage accumulation which accelerated PanIN progression to PDAC. Finally, treatment with the DNA damage-inducing reagent etoposide resulted in elevated cell death in NEMO-ablated PDAC cells compared to their NEMO-competent counterparts, indicative of a synthetic lethality paradigm.
Conclusions: NEMO exhibited both oncogenic and tumor-suppressive properties during PDAC development. Caution is suggested in therapeutic interventions targeting NF-κB, which may be detrimental during PanIN progression but beneficial post-PDAC development.
(© 2024. The Author(s).)
Methods: To elucidate the role of NF-κB, we ablated NF-κB essential modulator (NEMO), critical for conventional NF-κB signaling, in the pancreata of mice that develop precancerous lesions (KC mouse model). Secretagogue-induced pancreatitis by cerulein injections was utilized to promote inflammation and accelerate PDAC development.
Results: NEMO deletion reduced fibrosis and inflammation in young KC mice, resulting in fewer pancreatic intraepithelial neoplasias (PanINs) at later stages. Paradoxically, however, NEMO deletion accelerated the progression of these fewer PanINs to PDAC and reduced median lifespan. Further, analysis of tissue microarrays from human PDAC sections highlighted the correlation between reduced NEMO expression in neoplastic cells and poorer prognosis, supporting our observation in mice. Mechanistically, NEMO deletion impeded oncogene-induced senescence (OIS), which is normally active in low-grade PanINs. This blockage resulted in fewer senescence-associated secretory phenotype (SASP) factors, reducing inflammation. However, blocked OIS fostered replication stress and DNA damage accumulation which accelerated PanIN progression to PDAC. Finally, treatment with the DNA damage-inducing reagent etoposide resulted in elevated cell death in NEMO-ablated PDAC cells compared to their NEMO-competent counterparts, indicative of a synthetic lethality paradigm.
Conclusions: NEMO exhibited both oncogenic and tumor-suppressive properties during PDAC development. Caution is suggested in therapeutic interventions targeting NF-κB, which may be detrimental during PanIN progression but beneficial post-PDAC development.
(© 2024. The Author(s).)