Targeting the extracellular HSP90 co-chaperone Morgana inhibits cancer cell migration and promotes anti-cancer immunity

Heat shock protein 90 (HSP90) is secreted by cancer cells into the extracellular milieu, where it exerts pro-tumoral activities by activating extracellular substrate proteins and triggering autocrine signals through cancer cell surface receptors. Emerging evidence indicates that HSP90 co-chaperones are also secreted and may direct HSP90 extracellular activities. In this study, we found that the HSP90 co-chaperone Morgana is released by cancer cells and, in association with HSP90, induces cancer cell migration through TLR2, TLR4, and LRP1. In syngeneic cancer mouse models, a monoclonal antibody targeting Morgana extracellular activity reduced primary tumor growth via macrophage-dependent recruitment of CD8+ T lymphocytes, blocked cancer cell migration, and inhibited metastatic spreading. Overall, this data defines Morgana as a new player in the HSP90 extracellular interactome and suggests that Morgana may regulate HSP90 activity to promote cancer cell migration and suppress anti-tumor immunity.