Scantamburlo Francesca, Rubini Alessia, Toffanin Margherita, Castorina Maria Egle, Ciscato Francesco, Tomasoni Sofia, Finotti Paolo, Verin Ranieri, Zappulli Valentina, Fantuz Marco, Bean Camilla, Rasola Andrea, Masgras Ionica
Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58/B, Padova, 35131, Italy.
Institute of Neuroscience, National Research Council, via Ugo Bassi 58/B, Padova, 35131, Italy.
J Exp Clin Cancer Res. 2025 Aug 28;44(1):257. doi: 10.1186/s13046-025-03525-1.
Metabolic adaptations can sustain the pro-neoplastic functions exerted by macrophages in the tumor microenvironment. Malignant peripheral nerve sheath tumors (MPNSTs), aggressive and incurable sarcomas that develop either sporadically or in the context of the genetic syndrome Neurofibromatosis type 1, are highly infiltrated by macrophages, whose contribution to MPNST growth remains poorly characterized. Here, we analyze the role played by the molecular chaperone TRAP1, a regulator of mitochondrial metabolic pathways, in shaping the pro-tumoral activity of macrophages associated to MPNST cells.
We have studied the phenotypic changes elicited by a MPNST cell-conditioned medium in macrophages with or without TRAP1, and their subsequent ability to support MPNST cell growth and migration and endothelial cell angiogenesis.
The presence of TRAP1 is required in both naive and M2-like macrophages for eliciting phenotypic changes that lead to the acquisition of pro-neoplastic features. TRAP1-expressing macrophages become able to sustain MPNST cell growth and migration and to exert pro-angiogenic properties on endothelial cells through accumulation of the metabolite succinate and the ensuing activation of a HIF-1α-dependent transcriptional program.
Our data provide evidence of a molecular crosstalk between MPNST cellular components, in which soluble factors released by cancer cells drive phenotypic changes in macrophages that in turn enhance pro-tumoral biological routines in both MPNST and endothelial cells. TRAP1-dependent metabolic rewiring in macrophages is mandatory for sustaining this interplay, as a TRAP1-succinate-HIF-1α signaling axis orchestrates their acquisition of tumor-promoting features.
代谢适应能够维持巨噬细胞在肿瘤微环境中发挥的促肿瘤功能。恶性外周神经鞘瘤（MPNSTs）是一种侵袭性且无法治愈的肉瘤，可散发发生或在1型神经纤维瘤病遗传综合征背景下发生，其巨噬细胞浸润程度很高，而巨噬细胞对MPNST生长的作用仍不清楚。在此，我们分析了分子伴侣TRAP1（线粒体代谢途径的调节因子）在塑造与MPNST细胞相关的巨噬细胞促肿瘤活性中所起的作用。
我们研究了MPNST细胞条件培养基在有或没有TRAP1的巨噬细胞中引发的表型变化，以及它们随后支持MPNST细胞生长、迁移和内皮细胞血管生成的能力。
在幼稚巨噬细胞和M2样巨噬细胞中，TRAP1的存在都是引发导致获得促肿瘤特征的表型变化所必需的。表达TRAP1的巨噬细胞能够维持MPNST细胞的生长和迁移，并通过代谢物琥珀酸的积累以及随后激活HIF-1α依赖性转录程序，对内皮细胞发挥促血管生成特性。
我们的数据提供了MPNST细胞成分之间分子串扰证据，其中癌细胞释放的可溶性因子驱动巨噬细胞的表型变化，进而增强MPNST和内皮细胞中的促肿瘤生物学过程。巨噬细胞中TRAP1依赖性代谢重编程对于维持这种相互作用是必不可少的，因为TRAP1-琥珀酸-HIF-1α信号轴协调了它们获得促肿瘤特征的过程。
