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.

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

Seclì, Laura
First
;
Avalle, Lidia;Poggio, Pietro;Fragale, Giuseppe;Cannata, Cristiana;Conti, Laura;Carrà, Giovanna;Rubinetto, Cristina;Miniscalco, Barbara;Hirsch, Emilio;Poli, Valeria;Morotti, Alessandro;De Andrea, Marco;Turco, Emilia;Cavallo, Federica;Fusella, Federica;Brancaccio, Mara
Last
2021

Abstract

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.
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Seclì, Laura; Avalle, Lidia; Poggio, Pietro; Fragale, Giuseppe; Cannata, Cristiana; Conti, Laura; Iannucci, Andrea; Carrà, Giovanna; Rubinetto, Cristina; Miniscalco, Barbara; Hirsch, Emilio; Poli, Valeria; Morotti, Alessandro; De Andrea, Marco; Turco, Emilia; Cavallo, Federica; Fusella, Federica; Brancaccio, Mara
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1806663
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