The role of IFIT3 for the pro-inflammatory microenvironment of pancreatic cancer pathogenesis

• Applicant: Professorin Dr. Christiane Josephine Bruns
• Subject Area: General and Visceral Surgery
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 316568276

• Final Report Year: 2021

Final Report Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide, while effective therapies still remain a big challenge. Though IFIT3 is one of the interferon-stimulated genes with antiviral and pro-inflammatory functions, recent studies demonstrated its role in tumor progression and prediction of treatment response. The major findings of this project are the following aspects: 1. The distribution of the IFIT3 expression in PDAC is not homogeneous. 2. Four centers provided two different platforms to analyze the clinical relevance of IFIT3 in PDAC. In patients who received adjuvant chemotherapy we saw a statistically significant better survival in cases with negative or weak expression of IFIT3, low IFIT3 expression was associated with longer DFS in PDAC patients receiving neoadjuvant chemotherapy. Interestingly, IFIT3 scores of patients developing lung metastases were significantly lower compared to those developing liver metastases. 3. Using PDAC transcriptomic data we determine that IFIT3 expression is associated with a squamous subtype of PDAC and has an enrichment of inflammatory response and apoptosis pathways. 4. We revealed the crucial role of IFIT3 in the regulation of mitochondria-associated apoptosis during chemotherapy. Knockdown of IFIT3 attenuated chemotherapy resistance of PDAC cells to gemcitabine, paclitaxel, and FOLFIRINOX regimen treatments independent of chemotherapy regimens. 5. Co-immunoprecipitation identified the interaction of IFIT3 with the mitochondrial channel protein VDAC2, an important regulator of mitochondria-associated apoptosis. 6. IFIT3 regulated the post-translational modification-O-GlcNAcylation of VDAC2 by stabilizing the interaction of VDAC2 with OGT. We are the first group reporting the biological role of Interferon stimulating gene IFIT3 in PDAC. We have evaluated the clinical relevance of IFIT3 in PDAC associated with therapy response by a multi-center analysis by both tissue microarray and the comprehensive scoring of tumor cell and tumor stroma expression. For the first time, our data demonstrates a new mechanism of IFIT3 interacting with VDAC2 rendering chemotherapy resistance in PDAC. Targeting IFIT3/VDAC2 might be therefore considered as a potential new strategy to sensitize PDAC against conventional chemotherapy regimens. In the future, the role of IFIT3 in the tumor microenvironment and the IFIT3 signaling in immunotherapy crosstalk deserve in-depth exploration.

Publications

• Elevated Interferoninduced protein with tetratricopeptide repeats 3 (IFIT3) is a poor prognostic marker in pancreatic ductal adenocarcinoma. Journal of Cancer Research and Clinical Oncology. 2017 Jun;143(6):1061-1068
  Yue Zhao, Annelore Altendorf-Hofmann, Ioannis Pozios, Peter Camaj, Therese Däberitz, Xiaoyan Wang, Hanno Niess, Hendrik Seeliger, Felix Popp, Christopher Betzler, Utz Settmacher, Karl-Walter Jauch, Christiane Bruns, Thomas Knösel
  
• Protocol of the PANCALYZE trial: a multicenter, prospective study investigating the tumor biomarkers CXCR4, SMAD4, SOX9 and IFIT3 in patients with resected pancreatic adenocarcinoma to predict the pattern of recurrence of the disease. BMC Cancer. 2017 Mar 29;17(1):229
  Popp FC, Popp MC, Zhao Y, Betzler C, Kropf S, Garlipp B, Benckert C, Kalinski T, Lippert H, Bruns CJ
  
• Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer. Cancers (Basel). 2019 Jun 22;11(6). pii: E874
  Zhao J, Schlö ßer HA, Wang Z, Qin J, Li J, Popp F, Popp MC, Alakus H, Chon SH, Hansen HP, Neiss WF, Jauch KW, Bruns CJ, Zhao Y
  
• Inflammatory IFIT3 renders chemotherapy resistance by regulating post-translational modification of VDAC2 in pancreatic cancer. Theranostics. 2020; 10(16):7178-7192
  Zhefang Wang, Jie Qin, Jiangang Zhao, Jiahui Li, Dai Li, Marie Popp, Felix Popp, Hakan Alakus, Bo Kong, Qiongzhu Dong, Peter J. Nelson, Yue Zhao, Christiane J. Bruns
  
• Interferon-Induced Protein With Multiple Tetratricopeptide Repeats 3 Is Associated With Response to Chemotherapy and Recurrence but Not With Survival. Pancreas. 2020 Nov/Dec;49(10):1307-1314
  Popp MC, Klippstein M, Lohneis P, Kalinski T, Li J, Quaas A, Bludau M, Wang Z, Waldschmidt D, Kunzmann V, Damanakis A, Gebauer F, Zhao Y, Bruns CJ, Popp FC
  
• The IL-17A/IL-17RA Axis Is Not Related to Overall Survival and Cancer Stem Cell Modulation in Pancreatic Cancer. Int J Mol Sci. 2020 Mar 23;21(6):2215
  Li J, Betzler C, Lohneis P, Popp MC, Qin J, Kalinski T, Wartmann T, Bruns CJ, Zhao Y, Popp FC