| Autor: |
Abu Bakar NDB; Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia., Carlessi R; Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia., Gogoi-Tiwari J; Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia., Köhn-Gaone J; Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia., Williams V; Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia., Falasca M; Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia., Olynyk JK; Fiona Stanley Hospital, Murdoch, WA 6150, Australia.; School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia., Ramm GA; QIMR Berghofer Institute, Brisbane, QLD 4006, Australia.; Faculty of Medicine, The University of Queensland, Brisbane, QLD 4006, Australia., Tirnitz-Parker JEE; Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia.; Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia. |
| Abstrakt: |
Chronic pancreatitis increases the risk of developing pancreatic cancer through the upregulation of pathways favouring proliferation, fibrosis, and sustained inflammation. We established in previous studies that the ligand tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) signals through its cognate receptor fibroblast growth factor-inducible 14 (Fn14) to regulate these underlying cellular processes in the chronic liver injury niche. However, the role of the TWEAK/Fn14 signalling pathway in pancreatic disease is entirely unknown. An analysis of publicly available datasets demonstrated that the TWEAK receptor Fn14 is upregulated in pancreatitis and pancreatic adenocarcinoma, with single cell RNA sequencing revealing pancreatic ductal cells as the main Fn14 producers. We then used choline-deficient, ethionine-supplemented (CDE) diet feeding of wildtype C57BL/6J and Fn14 knockout littermates to (a) confirm CDE treatment as a suitable model of chronic pancreatitis and (b) to investigate the role of the TWEAK/Fn14 signalling pathway in pancreatic ductal proliferation, as well as fibrotic and inflammatory cell dynamics. Our time course data obtained at three days, three months, and six months of CDE treatment reveal that a lack of TWEAK/Fn14 signalling significantly inhibits the establishment and progression of the tissue microenvironment in CDE-induced chronic pancreatitis, thus proposing the TWEAK/Fn14 pathway as a novel therapeutic target. |
