Extracellular chaperones induce cancer cell migration by bursting integrin endocytosis

Once released in the tumor microenvironment, the chaperone protein HSP90 induces cancer cell migration and promotes metastasis formation together with its co-chaperone Morgana. It is well known that the extracellular HSP90 (eHSP90) forms different protein complexes, likely endowed with different abilities to shape the tumor microenvironment. However, the precise molecular mechanism through which the eHSP90-eMorgana complex exerts its pro-tumoral activity remains unclear. Here I demonstrate that some of the eHSP90 complexes containing extracellular Morgana (eMorgana) induce tumor cell migration by regulating the reciprocal interactions of three cell surface receptors, LRP1 and TLR2 and 4. In tumor cells, the eHSP90-eMorgana complex stimulates TLR2-TLR4 heterodimerization, disengaging the endocytic receptor LRP1 from their binding. This reduced protein interplay in response to the eHSP90-eMorgana complex activates LRP1, which bursts integrin-β1 endocytosis and recycling through the Rab5 and Rab11 compartments, likely forming new focal adhesions and promoting migration. Intriguingly, the extracellular chaperone complex also supports extracellular matrix modification and, ultimately, cell invasion. Overall, these data depict an unprecedently described mechanism of action for extracellular chaperones promoting breast cancer cell migration and invasion.