Thyroid cancer-derived exosomal SPP1 promotes tumor progression by driving macrophage M2 polarization through the CD44/JAK2/STAT3 signaling pathway.

IF 6.3 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Organogenesis Pub Date : 2026-12-31 Epub Date: 2026-05-19 DOI:10.1080/15476278.2026.2670152

Jiwen Yang, Weili Yin, Junliang Ge, Guangjian Gao, Xinming Yao, Yayin Huang

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引用次数: 0

Abstract

Background: While secreted phosphoprotein 1 (SPP1) drives macrophage M2 polarization and cancer progression in multiple malignancies, its role in thyroid cancer remains poorly understand. This study investigated the roles and mechanisms of thyroid cancer-derived exosomal SPP1 in regulating macrophage M2 polarization and malignant progression in thyroid cancer.

Methods: SPP1 protein expression in thyroid cancer tissues and cell lines was assessed. Exosomes from TPC1 cells were isolated and characterized for SPP1 expression. THP-1 cell-differentiated M0 macrophages were treated with unmodified or SPP1-knockdown exosomes, followed by detection of M2 phenotype markers and analysis of cytokine secretion profiling in response to LPS stimulation. The conditioned macrophages were then co-cultured with thyroid cancer cells, and cell proliferation, migration and invasion were examined. Mechanistic studies focused on CD44/JAK2/STAT3 signaling using an anti-CD44 monoclonal antibody. Additionally, tumor growth and macrophage infiltration were assessed in a xenograft tumor mouse model following exosomal SPP1 knockdown.

Results: SPP1 was upregulated in thyroid cancer and enriched in TPC1-derived exosomes. These exosomes induced macrophage M2 polarization, thereby promoting cancer cell proliferation, migration and invasion. However, SPP1 knockdown in exosomes abolished these effects. Exosomal SPP1 directly interacted with CD44 receptors and activated the JAK2/STAT3 signaling pathway to drive M2 polarization. CD44 blockade reversed M2 polarization and pro-tumorigenic effects. SPP1-deficient exosomes reversed tumor growth and attenuated M2 macrophage infiltration in xenograft model.

Conclusions: Thyroid cancer-derived exosomal SPP1 promotes tumor progression by driving macrophage M2 polarization via the CD44/JAK2/STAT3 signaling pathway. The exosomal SPP1-CD44 axis represents a promising therapeutic target for thyroid cancer.

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甲状腺癌源性外泌体SPP1通过CD44/JAK2/STAT3信号通路驱动巨噬细胞M2极化，从而促进肿瘤进展。

背景：虽然分泌磷酸化蛋白1 （SPP1）在多种恶性肿瘤中驱动巨噬细胞M2极化和癌症进展，但其在甲状腺癌中的作用尚不清楚。本研究探讨甲状腺癌源性外泌体SPP1在调节巨噬细胞M2极化和甲状腺癌恶性进展中的作用和机制。方法：检测SPP1蛋白在甲状腺癌组织和细胞系中的表达。从TPC1细胞中分离出外泌体，并鉴定了SPP1的表达。用未修饰或敲低spp1的外泌体处理THP-1细胞分化的M0巨噬细胞，然后检测M2表型标记并分析细胞因子分泌谱对LPS刺激的响应。将条件巨噬细胞与甲状腺癌细胞共培养，观察细胞增殖、迁移和侵袭情况。机制研究主要集中在CD44/JAK2/STAT3信号通路上，使用抗CD44单克隆抗体。此外，在外泌体敲除SPP1后，在异种移植肿瘤小鼠模型中评估肿瘤生长和巨噬细胞浸润。结果：SPP1在甲状腺癌中表达上调，并在tpc1衍生的外泌体中富集。这些外泌体诱导巨噬细胞M2极化，从而促进癌细胞的增殖、迁移和侵袭。然而，外泌体中SPP1的敲除消除了这些作用。外泌体SPP1直接与CD44受体相互作用，激活JAK2/STAT3信号通路，驱动M2极化。CD44阻断逆转M2极化和促肿瘤作用。在异种移植模型中，spp1缺陷外泌体逆转肿瘤生长并减弱M2巨噬细胞浸润。结论：甲状腺癌源性外泌体SPP1通过CD44/JAK2/STAT3信号通路驱动巨噬细胞M2极化，从而促进肿瘤进展。外泌体SPP1-CD44轴是甲状腺癌的一个有希望的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Organogenesis BIOCHEMISTRY & MOLECULAR BIOLOGY-DEVELOPMENTAL BIOLOGY

CiteScore

4.10

自引率

4.30%

发文量

审稿时长

>12 weeks

期刊介绍： Organogenesis is a peer-reviewed journal, available in print and online, that publishes significant advances on all aspects of organ development. The journal covers organogenesis in all multi-cellular organisms and also includes research into tissue engineering, artificial organs and organ substitutes. The overriding criteria for publication in Organogenesis are originality, scientific merit and general interest. The audience of the journal consists primarily of researchers and advanced students of anatomy, developmental biology and tissue engineering. The emphasis of the journal is on experimental papers (full-length and brief communications), but it will also publish reviews, hypotheses and commentaries. The Editors encourage the submission of addenda, which are essentially auto-commentaries on significant research recently published elsewhere with additional insights, new interpretations or speculations on a relevant topic. If you have interesting data or an original hypothesis about organ development or artificial organs, please send a pre-submission inquiry to the Editor-in-Chief. You will normally receive a reply within days. All manuscripts will be subjected to peer review, and accepted manuscripts will be posted to the electronic site of the journal immediately and will appear in print at the earliest opportunity thereafter.