Document Type

Journal Article

Publication Title

Cancers

Volume

15

Issue

6

Publisher

MDPI

School

School of Medical and Health Sciences

RAS ID

56576

Funders

National Health and Medical Research Council / Australian Government-funded RTP PhD scholarship (N.D.B.A.B.) / Cancer Council of WA Early Career Fellowship (R.C.)

Grant Number

NHMRC : APP1087125, APP1160323

Grant Link

http://purl.org/au-research/grants/nhmrc/1087125

Comments

Abu Bakar, N. D. B., Carlessi, R., Gogoi-Tiwari, J., Köhn-Gaone, J., Williams, V., Falasca, M., ... & Tirnitz-Parker, J. E. (2023). TWEAK/Fn14 signalling regulates the tissue microenvironment in chronic pancreatitis. Cancers, 15(6), Article 1807. https://doi.org/10.3390/cancers15061807

Abstract

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.

DOI

10.3390/cancers15061807

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Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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