The cytokine MIF as a promoter of colorectal cancer

• Applicant: Privatdozentin Dr. Ramona Schulz-Heddergott, Ph.D.
• Subject Area: Hematology, Oncology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 380155865

MIF (macrophage migration inhibitory factor) was originally discovered as a secreted pro-inflammatory cytokine with a central role in innate immunity. Over the last two decades, MIF has also been strongly implicated as a tumor promoter. Importantly, MIF not only acts in the epithelial cancer cell compartment, but also in the associated stromal fibroblasts and cells of the immune system. The tumor promoting activities of MIF correlate with tumor aggressiveness and poor clinical prognosis. Independent of the histological tumor type, MIF is highly elevated in cancer cells. Elevated MIF levels are also strongly correlated with colorectal cancer (CRC) progression in patients. However, to date no experimental model has established a causative role of MIF in CRC development and progression in order to assess MIF as rational target for anti-cancer therapies. To rigorously test whether constitutive MIF levels are essential for maintenance of colorectal tumors, we will analyze an inducible conditional MIF knock-out system in a chemically-induced CRC model. Importantly, we will use a wtp53-deficient mouse background to increase the aggressive behavior of our model system. Thus, MIF will be depleted after tumors have started growing and tumor progression will be visualized by colonoscopy in longitudinal studies. We will analyze whether MIF is required for tumor survival, angiogenesis and invasion. With respect to anti-cancer therapies, we will further assess a pharmacological approach to target MIF. Recently, we showed that MIF is stabilized and elevated by the heat-shock protein 90 protein (HSP90). HSP90 inhibition (HSP90i) strongly decreases MIF levels and kills human cancer cells. Because of these findings, clinically advanced HSP90i will be used to treat CRC in mice followed by the analysis of their therapeutic response. We expect to recapitulate the effect of genetic MIF depletion with a pharmacological HSP90i. This would establish a promising MIF-based anticancer strategy.In sum, this project will use genetic and pharmacologic analyses to explore the role of MIF in CRC in vivo and establish MIF as a key target of HSP90 inhibitor-based CRC therapy.

• DFG Programme: Research Grants