A Novel MIF-driven Signaling Drives Disease Aggressiveness by Targeting NR3C2 in Pancreatic Ductal Adenocarcinoma

Authors

• S Yang
• P He
• J Wang
• A Schetter
• W Tang
• N Funamizu
• K Yanaga
• T Uwagawa
• AR Satoskar
• J Gaedcke
• M Bernhardt
• BM Ghadimi
• MM Gaida
• F Bergmann
• J Werner
• T Ried
• N Hanna
• HR Alexander
• SP Hussain

Abstract

Objective: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Pancreatic tumors with aberrant expression of macrophage migration inhibitory factor (MIF) are highly aggressive, and an increased MIF predicts poorer patient survival. We conducted molecular characterization of pancreatic tumors, expressing high level of MIF, and investigated the mechanistic and functional role of MIF in disease aggressiveness, and assessed its potential as therapeutic target. Design: We analyzed the expression of coding and non-coding genes in high and low MIF-expressing tumors in multiple cohorts of PDAC patients to identify key signaling pathways that drive disease aggressiveness in tumors with high MIF expression. The identified key genes and pathways were linked to patients’ survival and were mechanistically, functionally and clinically characterized using cell lines, genetically engineered mouse model and PDAC patient cohorts. Results: MIF upregulated miR-301b, which then targeted and inhibited a previously undescribed tumor suppressor, nuclear-receptor-subfamily-3, group-C, member-2 (NR3C2). Tumors with high MIF expression showed an elevated miR-301b and a reduced NR3C2 expression. Additionally, patients with a lower NR3C2 expression in tumors showed poorer survival. NR3C2 inhibited epithelial-to-mesenchymal transition and enhanced sensitivity to chemotherapeutic drug gemcitabine. Furthermore, genetic deletion of MIF disrupted MIF-mir-301b-NR3C2 axis, which resulted in reduced metastasis and prolonged survival in genetically engineered mouse model of PDAC. Conclusions: We identified a novel MIF-induced signaling pathway, which drives pancreatic cancer aggressiveness by inhibiting a previously undescribed tumor suppressor NR3C2. Our findings also provide proof-of-concept that therapies targeting MIF-miR-301b-NR3C2 axis may improve disease outcome in patients with PDAC.

Scientific Focus Area: Cancer Biology

This page was last updated on Friday, March 26, 2021