TRAP1 expression elicits pro-tumoral functions in macrophages associated to malignant peripheral nerve sheath tumor cells.

IF 12.8 1区 医学 Q1 ONCOLOGY
Francesca Scantamburlo, Alessia Rubini, Margherita Toffanin, Maria Egle Castorina, Francesco Ciscato, Sofia Tomasoni, Paolo Finotti, Ranieri Verin, Valentina Zappulli, Marco Fantuz, Camilla Bean, Andrea Rasola, Ionica Masgras
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引用次数: 0

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

TRAP1的表达在与恶性周围神经鞘肿瘤细胞相关的巨噬细胞中引发促瘤功能。
背景:代谢适应可以维持巨噬细胞在肿瘤微环境中发挥的促肿瘤功能。恶性周围神经鞘肿瘤(MPNSTs)是一种侵袭性的、无法治愈的肉瘤,它要么是偶发的,要么是在遗传综合征1型神经纤维瘤病的背景下发生的,它被巨噬细胞高度浸润,巨噬细胞对MPNST生长的贡献仍不清楚。在这里,我们分析了分子伴侣TRAP1(线粒体代谢途径的调节剂)在形成与MPNST细胞相关的巨噬细胞的促肿瘤活性中所起的作用。方法:我们研究了MPNST细胞条件培养基在含或不含TRAP1的巨噬细胞中引起的表型变化,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。结果:在初始巨噬细胞和m2样巨噬细胞中,TRAP1的存在都需要引起表型变化,从而获得促肿瘤特征。通过代谢产物琥珀酸盐的积累和随后hif -1α依赖性转录程序的激活,表达trap1的巨噬细胞能够维持MPNST细胞的生长和迁移,并对内皮细胞发挥促血管生成特性。结论:我们的数据提供了MPNST细胞组分之间的分子串扰的证据,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和内皮细胞的促肿瘤生物学常规。巨噬细胞中trap1依赖性的代谢重布线对于维持这种相互作用是必需的,因为trap1 -琥珀酸- hif -1α信号轴协调它们获得肿瘤促进特征。
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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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