Expression of Irf3 and Irf7 in tumour cells drives pancreatic cancer development and progression
Recommended Citation
Fahr L, Benitz S, Straub T, Mutter J, Lisiecki H, Mahajan UM, Beyer G, Steiger K, Terrasi A, Schotta G, Imhof A, Lauber K, Kleeff J, Michalski CW, Mayerle J, Regel I. Expression of Irf3 and Irf7 in tumour cells drives pancreatic cancer development and progression. Pancreatology 2023; 23:e134-e135.
Document Type
Conference Proceeding
Publication Date
11-5-2023
Publication Title
Pancreatology
Abstract
Abstract Background: The interferon regulatory factors 3 and 7 (Irf3 and Irf7) are transcription factors downstream of the Toll-like receptor 3 (Tlr3) signalling pathway. Tlr3 signalling is stimulated by double-stranded RNAs, which are generated during viral infections but also during tissue stress and cell injury. In previous studies, we found Tlr3, Irf3, and Irf7 to be overexpressed in metaplastic acinar cells and pancreatic tumour cells. The purpose of this project is to investigate the functional role of Irf3 and Irf7 in pancreatic carcinogenesis, particularly in non-immune cells. Methods: Pancreatic tumourigenesis was examined at various time points in caerulein-treated Irf3/Irf7 knockout mice with inducible Kras mutation. Furthermore, we generated Tlr3-hyperactivated and Irf3/Irf7 double knockout murine pancreatic tumour cells. These tumour cells were phenotypically characterised in vitro and further used in orthotopic and metastatic mouse models. Additionally, we identified transcriptional alterations in Irf3/Irf7 knockout tumour cells by RNA-Seq. Results: Global loss of Irf3/Irf7 prevents the formation of precursor lesions and pancreatic cancer in caerulein-treated Kras mutant mice. Consequently, depletion of Irf3 and Irf7 in tumour cells leads to reduced invasive capacity and decreased colony formation in vitro. In the orthotopic and metastatic mouse models, injection of Irf3/Irf7 knockout cells markedly impaired tumour and metastasis formation, whereas Tlr3-hyperactivated cells led to increased tumour and metastasis volumes. Our in vivo and in vitro experiments confirmed an immune-independent function of the Tlr3/Irf3/Irf7 signalling pathway in pancreatic tumour cells that is crucial for tumour progression. Conclusion: Our findings suggest that Irf3 and Irf7 expression in tumour cells is required for the development of pancreatic cancer. Moreover, activated Tlr3/Irf3/Irf7 signalling enhances tumour cell aggressiveness in pancreatic cancer cells.
Medical Subject Headings
Hematology
PubMed ID
Not assigned.
Volume
23
First Page
e134
Last Page
e135
