Investigating the role of the mitochondrial chaperone TRAP1 in protumoral polarization of macrophages

Macrophages are immune cells present in all tissues that can be found also in different tumors with diverse functions. Tumor microenvironment can educate them toward proneoplastic functions, characterized by proangiogenic and proinvasive features that are driven by specific macrophage metabolic alterations. In cancer cells, such as Malignant Peripheral Nerve Sheath Tumor cells (MPNSTs), the mitochondrial chaperone TRAP1 can contribute to metabolic regulation through succinate mediated stabilization of HIF1α that induces protumoral gene transcription. However, the role played by TRAP1 in macrophage metabolic regulation is still unknown. This project aims to investigate whether TRAP1 has a role in macrophage polarization, thus enhancing their protumoral functions. The use of mouse bone-marrow derived macrophages has revealed that they undergo a proneoplastic polarization when exposed to MPNST cell media, as assessed by measuring phenotypic and functional features. Importantly, the onset of these changes is reduced when TRAP1 expression is knocked out in macrophages. Succinate administration rescues the protumoral functions of these cells, suggesting the presence of a mechanistic link between TRAP1 and HIF1α that is crucial for the proneoplastic functions of macrophages. These findings indicate that the chaperone TRAP1 is a crucial regulator of macrophage metabolism, paving the way for novel therapeutic approaches aiming at hitting macrophages in the MPNST microenvironment.