PO.CH02.01 · 化学
整合素alphavbeta3驱动的分泌组重塑揭示THBS1为皮肤T细胞淋巴瘤中潜在的预后介导因子
Integrin alphavbeta3-driven secretome remodeling uncovers THBS1 as a potential prognostic mediator in cutaneous T-cell lymphoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
皮肤T细胞淋巴瘤（CTCL）是一组异质性的T细胞非霍奇金淋巴瘤，其进展依赖于与肿瘤微环境的动态相互作用。甲状腺激素（THs）在生理浓度下通过膜受体整合素alphavbeta3激活致癌信号，如MAPK和JAK/STAT，从而促进T细胞淋巴瘤的增殖和播散。然而，该通路对CTCL分泌组的影响及其对疾病进展的贡献仍缺乏充分表征。在此，我们使用蕈样肉芽肿（MJ）和Sézary综合征（HuT78）细胞系，在有或没有alphavbeta3抑制剂西仑吉肽（cilengitide，1.5 μM）的条件下，用THs（T4=100 nM，T3=1 nM）进行处理，分析整合素alphavbeta3激活如何调控CTCL分泌组。通过LC-MS/MS分析分泌至上清液中的蛋白，并使用limma和ShinyGO评估差异表达。在基础条件下，与MJ相比，HuT78分泌组表现出更具侵袭性的特征，富集于血管生成、代谢重编程和免疫逃逸通路。TH处理显著改变了两种模型的分泌组组成，在HuT78中有66种蛋白上调、54种蛋白下调（FDR <0.1）。富集的通路包括VEGFA-VEGFR2、局部黏附和TGF-beta信号通路，这些均与肿瘤播散和免疫抑制性重塑相关。THBS1、FN1、FLNA、FLNB和TLN1位居上调最显著的蛋白之列，它们在功能上与细胞外基质组织、内皮激活以及抗肿瘤免疫抑制相关。重要的是，用西仑吉肽阻断整合素alphavbeta3逆转了TH诱导的这些蛋白上调，证明了其对整合素的依赖性。对CTCL患者数据集（GSE113113、GSE168508）的转录组学分析显示，THBS1蛋白的表达与ITGB3呈正相关（p<0.05），并在疾病晚期显著升高，与较差的生存结局相一致。总之，我们的结果表明，THs对整合素alphavbeta3的生理性激活将CTCL分泌组重塑为促肿瘤和免疫抑制状态。THBS1在该网络中成为潜在的预后介导因子，凸显了激素等全身性因素如何影响淋巴瘤进展，并揭示了具有诊断和治疗意义的新分子靶点。
查看英文原文 English abstract
Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of T-cell non-Hodgkin lymphomas whose progression depends on dynamic interactions with the tumor microenvironment. Thyroid hormones (THs), at physiological concentrations, act through the membrane receptor integrin alphavbeta3 to activate oncogenic signaling such as MAPK and JAK/STAT, promoting proliferation and dissemination in T-cell lymphomas. However, the impact of this pathway on the CTCL secretome and its contribution to disease progression remain poorly characterized. Here, we analyzed how integrin alphavbeta3 activation modulates the CTCL secretome using Mycosis Fungoides (MJ) and Sézary Syndrome (HuT78) cell lines treated with THs (T4=100 nM, T3=1 nM) with or without the alphavbeta3 inhibitor cilengitide (1.5 μM). Proteins secreted into supernatants were analyzed by LC-MS/MS, and differential expression was evaluated using limma and ShinyGO. Under basal conditions, HuT78 secretome displayed a more aggressive profile, enriched in angiogenesis, metabolic reprogramming, and immune evasion pathways compared to MJ. TH treatment significantly altered the secretome composition in both models, with 66 proteins upregulated and 54 downregulated in HuT78 (FDR <0.1). Enriched pathways included VEGFA-VEGFR2, focal adhesion, and TGF-beta signaling, all of which are associated with tumor dissemination and immunosuppressive remodeling. THBS1, FN1, FLNA, FLNB, and TLN1 were among the top upregulated proteins and are functionally related to extracellular matrix organization, endothelial activation, and inhibition of antitumor immunity. Importantly, integrin alphavbeta3 blockade with cilengitide reversed the TH-induced upregulation of these proteins, demonstrating integrin dependence. Transcriptomic analysis of CTCL patient datasets (GSE113113, GSE168508) revealed that the expression of protein THBS1 positively correlates with ITGB3 (p<0.05) and is significantly increased in advanced disease stages, consistent with poorer survival. Together, our results show that physiological activation of integrin alphavbeta3 by THs reshapes the CTCL secretome toward a pro-tumorigenic and immunosuppressive state. THBS1 emerges as a potential prognostic mediator within this network, underscoring how systemic factors like hormones can influence lymphoma progression and revealing new molecular targets with diagnostic and therapeutic relevance.
利益披露 Disclosure
M. M. Debernardi, None..
L. Alvarado, None..
I. Souza, None..
K. Formoso, None..
G. Cremaschi, None..
A. Correa Dominguez, None..
F. Cayrol, None.