EXPLORING TRAP1 AS A NOVEL REGULATOR OF MACROPHAGES ASSOCIATED TO MALIGNANT PERIPHERAL NERVE SHEATH TUMORS

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive sarcomas resistant to conventional therapies and endowed with a poor prognosis. Emerging research has highlighted critical metabolic adaptations of MPNST cells, disclosing the possibility of novel therapeutic approaches. In line with these observations, we have previously demonstrated that MPNSTs are characterized by an enhanced expression of the mitochondrial chaperone TRAP1, which inhibits the enzyme succinate dehydrogenase (SDH) leading to succinate accumulation thereby stabilizing the hypoxia-inducible factor 1 alpha (HIF-1α), a key driver of MPNST tumorigenesis. However, targeting only cancer cells is often insufficient to eradicate the most aggressive tumor types, as these require for their growth a number of interactions with microenvironmental components. Among these, tumor associated macrophages (TAMs) have garnered particular attention. Indeed, these cells have the potential to eliminate tumor cells (M1-like polarized TAMs), but have also been implicated in various processes supporting tumor growth (M2-like polarized TAMs). This polarization process is driven by the activation of specific metabolic pathways within TAMs, including the succinate-HIF-1α axis. Importantly, recent investigations show that MPNSTs are strongly infiltrated by TAMs characterized by a tumor sustaining M2-like phenotype. However, it is unknown which signals drive TAM polarization in these malignancies, and how TAMs contribute to their growth and progression. My working hypothesis is that TRAP1, acting as a bioenergetic rheostat and impinging on HIF-1α stabilization, could play a crucial role in the metabolic regulation of TAMs, thereby driving their polarization toward a tumor-promoting M2-like state. Here, through a combination of phenotypic and transcriptomic analyses, along with in vitro and in vivo assays, I have demonstrated that TRAP1-deficient TAMs do not express M2-like markers when exposed to MPNST-cell conditioned media, and exhibit a markedly reduced ability to promote tumor cell migration and angiogenesis through succinate accumulation and HIF-1α stabilization. Altogether, my data indicate that TRAP1 has a critical role in supporting the transition of macrophages into M2-like TAMs driven by MPNST cells, and in shaping their pro-tumorigenic functions. Therefore, my results suggest that targeting TRAP1 in TAMs could represent a promising therapeutic strategy, potentially disrupting crucial tumor-supportive pathways in MPNST microenvironment. This study opens new avenues for developing treatments that not only target the tumor cells themselves but also the critical immune components that contribute to MPNST progression.