Hsp90-stabilized MIF supports tumor progression via macrophage recruitment and angiogenesis in colorectal cancer

• DOI: 10.1038/s41419-021-03426-z
• Publication Date: 2021-02-04T13:06:58Z
• Authors: Luisa Klemke; Tiago De Oliveira; Daria Witt; Nadine Winkler; Hanibal Bohnenberger; Richard Bucala; Lena-Christin Con...; Ramona Schulz-Hed...
• Keywords: Tumor progression

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