This study highlights the importance of pathological reporting and suggests that tumor growth patterns and thorough examination but not surgical technique determine R1 resection rates in PDAC.

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Pancreatic cancers with aberrant expression of macrophage migration inhibitory factor (MIF) are particularly aggressive. To identify key signaling pathways that drive disease aggressiveness in tumors with high MIF expression, we analyzed the expression of coding and non-coding genes in high and low MIF-expressing tumors in multiple cohorts of pancreatic ductal adenocarcinoma (PDAC) patients. The key genes and pathways identified were linked to patient survival and were mechanistically, functionally and clinically characterized using cell lines, a genetically engineered mouse model and PDAC patient cohorts. Here we report evidence of a novel MIF-driven signaling pathway that inhibits the orphan nuclear receptor NR3C2, a previously undescribed tumor suppressor that impacts aggressiveness and survival in PDAC. Mechanistically, MIF upregulated miR-301b which targeted NR3C2 and suppressed its expression. PDAC tumors expressing high levels of MIF displayed elevated levels of miR-301b and reduced levels of NR3C2. Additionally, reduced levels of NR3C2 expression correlated with poorer survival in multiple independent cohorts of PDAC patients. Functional analysis showed that NR3C2 inhibited epithelial-to-mesenchymal transition and enhanced sensitivity to the gemcitabine, a chemotherapeutic drug used in PDAC standard of care. Furthermore, genetic deletion of MIF disrupted a MIF-mir-301b-NR3C2 signaling axis, reducing metastasis and prolonging survival in a genetically engineered mouse model of PDAC. Taken together, our results offer a preclinical proof-of-principle for candidate therapies to target a newly described MIF-miR-301b-NR3C2 signaling axis for PDAC management.

A newly defined prognostic profiling including the revised R1-definition discriminates survival of patients with resectable pancreatic adenocarcinoma better than the AJCC staging system, and may be of particular relevance for patient-adjusted therapy in the heterogeneous group of AJCC stage II tumors.