PO.CL05.10 · 临床研究
受SPRED2调控的外泌体通过激活IL6/STAT3信号重塑肿瘤微环境
Exosomes, regulated by SPRED2, reshape tumor microenvironment via activating IL6/ STAT3 signaling
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
SPRED2（Sprouty相关的、含EVH1结构域的蛋白2）是Ras依赖性ERK1/2信号的负性调节因子。我们此前的研究揭示，SPRED2通过SPRED2/p53/miR-506-3p/KLF4信号轴限制癌症干性，从而抑制肝细胞癌（HCC）进展。SPRED2缺失增强了HCC细胞的增殖、侵袭和化疗耐药，凸显了其肿瘤抑制作用。为进一步阐明SPRED2在肿瘤生物学中的更广泛作用，我们将关注点从HCC中的细胞内信号转向肿瘤微环境内的细胞间通讯。以食管鳞状细胞癌（ESCC）为模型，我们证明SPRED2通过调控多囊泡体（MVB）相关蛋白VAMP2和Syntaxin 4（STX4）来抑制外泌体分泌。外泌体是MVB与质膜融合后释放的纳米级囊泡，是癌症中细胞间信号传导的关键介质。SPRED2缺失显著增加了外泌体释放，提示SPRED2负性调控外泌体的生物发生和分泌。在功能上，ESCC来源的外泌体被发现携带具有生物活性的白细胞介素-6（IL-6），其通过两大机制促进肿瘤增殖和转移：激活ESCC细胞中的STAT3信号，以及诱导肿瘤微环境内的肿瘤相关巨噬细胞（TAM）极化。值得注意的是，SPRED2缺陷型ESCC细胞来源的外泌体增强了肿瘤细胞侵袭性和TAM极化，而SPRED2过表达细胞来源的外泌体对M1和M2巨噬细胞极化表现出抑制作用。极化的巨噬细胞反过来通过STAT3激活促进ESCC增殖和侵袭，在肿瘤细胞与免疫细胞之间建立了一个相互的前馈环路。此外，极化THP-1细胞来源的外泌体在体内显著加速了肿瘤进展，而这种效应被IL-6受体抑制剂Tocilizumab有效减弱。总之，我们的发现确认SPRED2是通过与VAMP2和STX4相互作用来调控外泌体生物发生和分泌的关键调节因子。通过控制富含IL-6的外泌体释放，SPRED2调节肿瘤-免疫细胞通讯并抑制促肿瘤微环境的形成，将其作用从癌症干性的细胞内抑制因子扩展为肿瘤-免疫相互作用的核心协调者。
查看英文原文 English abstract
SPRED2 (Sprouty-related, EVH1 domain-containing protein 2) is a negative regulator of Ras-dependent ERK1/2 signaling. Our previous studies revealed that SPRED2 suppresses hepatocellular carcinoma (HCC) progression by limiting cancer stemness through a SPRED2/p53/miR-506-3p/KLF4 signaling axis. Loss of SPRED2 enhanced proliferation, invasion, and chemoresistance in HCC cells, highlighting its tumor-suppressive role.To further elucidate the broader role of SPRED2 in tumor biology, we shifted our focus from intracellular signaling in HCC to intercellular communication within the tumor microenvironment. Using esophageal squamous cell carcinoma (ESCC) as a model, we demonstrated that SPRED2 suppresses exosome secretion by modulating multivesicular body (MVB)-associated proteins VAMP2 and Syntaxin 4 (STX4). Exosomes, nanosized vesicles released upon MVB-plasma membrane fusion, are critical mediators of intercellular signaling in cancer. Loss of SPRED2 markedly increased exosome release, suggesting that SPRED2 negatively regulates exosome biogenesis and secretion. Functionally, ESCC-derived exosomes were found to carry biologically active interleukin-6 (IL-6), which promotes tumor proliferation and metastasis through two major mechanisms: activation of STAT3 signaling in ESCC cells and induction of tumor-associated macrophage (TAM) polarization within the tumor microenvironment. Notably, exosomes derived from SPRED2-deficient ESCC cells enhanced both tumor cell aggressiveness and TAM polarization, whereas exosomes from SPRED2-overexpressing cells exhibited inhibitory effects on M1 and M2 macrophage polarization. The polarized macrophages, in turn, promoted ESCC proliferation and invasion via STAT3 activation, establishing a reciprocal feed-forward loop between tumor cells and immune cells. Furthermore, exosomes from polarized THP-1 cells significantly accelerated tumor progression in vivo, an effect that was effectively attenuated by Tocilizumab, an IL-6 receptor inhibitor.Collectively, our findings identify SPRED2 as a key regulator of exosome biogenesis and secretion through its interaction with VAMP2 and STX4. By controlling IL-6-enriched exosome release, SPRED2 modulates tumor-immune cell communication and suppresses the formation of a pro-tumorigenic microenvironment, extending its role from an intracellular suppressor of cancer stemness to a central coordinator of tumor-immune interactions.
利益披露 Disclosure
T. Gao, None..
A. Matsukawa, None.