Macrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity, but its expression is increased in some
cancers via stabilization with HSP90-associated chaperones. Here, we show that MIF stabilization is
tumor-specific in an acute
colitis-associated colorectal cancer (CRC) mouse model, leading to
tumor-specific functions and selective therapeutic vulnerabilities. Therefore, we demonstrate that a Mif deletion reduced CRC
tumor growth. Further, we define a dual role for MIF in CRC
tumor progression. Mif deletion protects mice from
inflammation-associated
tumor initiation, confirming the action of MIF on host inflammatory pathways; however, macrophage recruitment, neoangiogenesis, and proliferative responses are reduced in Mif-deficient
tumors once the
tumors are established. Thus, during neoplastic transformation, the function of MIF switches from a proinflammatory
cytokine to an angiogenesis promoting factor within our experimental model. Mechanistically, Mif-containing
tumor cells regulate angiogenic gene expression via a MIF/CD74/MAPK axis in vitro. Clinical correlation studies of CRC patients show the shortest overall survival for patients with high MIF levels in combination with CD74 expression. Pharmacological inhibition of HSP90 to reduce MIF levels decreased
tumor growth in vivo, and selectively reduced the growth of organoids derived from murine and human
tumors without affecting organoids derived from healthy epithelial cells. Therefore, novel, clinically relevant Hsp90 inhibitors provide therapeutic selectivity by interfering with tumorigenic MIF in
tumor epithelial cells but not in normal cells. Furthermore, Mif-depleted colonic
tumor organoids showed growth defects compared to wild-type organoids and were less susceptible toward HSP90 inhibitor treatment. Our data support that
tumor-specific stabilization of MIF promotes CRC progression and allows MIF to become a potential and selective therapeutic target in CRC.