Abu Bakar N Dianah B, Carlessi Rodrigo, Gogoi-Tiwari Jully, Köhn-Gaone Julia, Williams Vincent, Falasca Marco, Olynyk John K, Ramm Grant A, Tirnitz-Parker Janina E E
Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia.
Fiona Stanley Hospital, Murdoch, WA 6150, Australia.
Cancers (Basel). 2023 Mar 16;15(6):1807. doi: 10.3390/cancers15061807.
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.
慢性胰腺炎通过上调促进增殖、纤维化和持续性炎症的信号通路，增加了患胰腺癌的风险。我们在先前的研究中证实，配体肿瘤坏死因子（TNF）样凋亡弱诱导剂（TWEAK）通过其同源受体成纤维细胞生长因子诱导14（Fn14）发出信号，以调节慢性肝损伤微环境中的这些潜在细胞过程。然而，TWEAK/Fn14信号通路在胰腺疾病中的作用完全未知。对公开数据集的分析表明，TWEAK受体Fn14在胰腺炎和胰腺腺癌中上调，单细胞RNA测序显示胰腺导管细胞是主要的Fn14产生细胞。然后，我们对野生型C57BL/6J和Fn14基因敲除的同窝小鼠采用胆碱缺乏、乙硫氨酸补充（CDE）饮食喂养，以（a）确认CDE治疗是慢性胰腺炎的合适模型，以及（b）研究TWEAK/Fn14信号通路在胰腺导管增殖以及纤维化和炎症细胞动态变化中的作用。我们在CDE治疗的三天、三个月和六个月时获得的时间进程数据显示，缺乏TWEAK/Fn14信号显著抑制了CDE诱导的慢性胰腺炎中组织微环境的建立和进展，从而提出TWEAK/Fn14通路作为一个新的治疗靶点。
