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

Melusin: A cardioprotective chaperone able to modulate lipid metabolism and ROS production in the heart

Melusin is a small-chaperone protein, selectively expressed in the heart and skeletal muscles. In the heart, melusin plays a broad protective role, protecting cardiomyocytes from apoptotic death and sustaining the compensatory myocardial hypertrophy. We recently demonstrated that melusin is able to regulate the activity of the mitochondrial trifunctional protein (MTP), the protein complex responsible for fatty acids β-oxidation in mitochondria, modulating the cardiac metabolism in physiologic and stressconditions. We analyzed the myocardial metabolism and the redox state of mitochondria in mice null and transgenic for melusin in physiologic condition and under stress, induced by transverse aortic constriction or injection of doxorubicin. Our results suggest that melusin is able to balance the lipid metabolism and the ROS production in the heart, ameliorating the cardiac response to stress stimuli. Further studies may allow to find new therapeutic targets and approaches eligible for the treatment of cardiac diseases

The IKK/NF-κB signaling pathway requires Morgana to drive breast cancer metastasis

NF-κB regulates inflammation, cell survival, proliferation, and metastasis and is often hyperactivated in triple-negative breast cancer. Here the authors show that Morgana, a protein highly expressed in triple-negative breast cancers, drives NF-kB activation to promote metastasis and neutrophil recruitment