血小板衍生生长因子受体-β/小窝蛋白-1通过激活mTOR/FIP200/自噬相关蛋白13诱导癌症相关成纤维细胞自噬，促进乳腺癌的恶性进展。

PDGFR-β/Cav1-induced autophagy via mTOR/FIP200/ATG13 activation in cancer-associated fibroblasts promotes the malignant progression of breast cancer.

作者信息

Zhang Lifang, Wang Keqin, Zhang Jianbo, Qian Xianzhe, Zhang Xiaoan, Wang Yi, Hu Quan, Zhan Ziyi, Hu Wending, Lin Hui, Liu Xiaoming, Xiong Lixia

机构信息

The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.

First Clinical Medical College, Nanchang University, Nanchang, 330006, China.

出版信息

J Transl Med. 2025 Jul 11;23(1):784. doi: 10.1186/s12967-025-06831-6.

DOI:10.1186/s12967-025-06831-6

PMID:40646615

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12247457/

Abstract

BACKGROUND

Breast cancer incidence rates have been increasing globally. Cancer-associated fibroblasts (CAFs), key stromal components of the tumor microenvironment (TME), play crucial roles in tumor growth by dynamically interacting with cancer cells. Autophagy has been extensively studied in multiple stages of the metastatic cascade. However, the roles of two key membrane proteins, platelet-derived growth factor receptor-β (PDGFR-β) and caveolin-1 (Cav-1), in regulating autophagy in CAFs and their effects on cancer cell invasion and migration remain unclear.

METHODS

The association between PDGFR-β expression and clinical features in breast cancer patients was analyzed using TCGA databases. PDGFR-β was either overexpressed or pharmacologically inhibited in cancer cells. Autophagy-related markers and signaling proteins were analyzed by Western blot and RT-qPCR, while lactate secretion and ROS levels were quantified. Breast cancer cell migration and invasion were evaluated through wound healing and transwell assays, and PDGFR-β/Cav1 interactions were verified by immunofluorescence and co-immunoprecipitation (Co-IP). A breast cancer mouse model was employed to assess tumor progression and autophagy modulation in vivo.

RESULTS

The study demonstrated that PDGFR-β promotes autophagy in CAFs through the mTOR/FIP200/ATG13 signaling. PDGFR-β/Cav-1 enhanced glycolysis in CAFs via autophagy-mediated metabolic reprogramming, resulting in increased lactate export that promoted breast cancer cell growth. Furthermore, CAFs autophagy regulated breast cancer cell invasion and migration via the HIF-1α/MCT4/MCT1 signaling pathway. These findings reveal that PDGFR-β/Cav-1-mediated autophagy in CAFs enhances breast cancer cell invasion, migration, and epithelial-mesenchymal transition (EMT), collectively highlighting the crucial role of CAFs autophagy in facilitating breast cancer progression.

CONCLUSIONS

The study elucidates the mechanism by which PDGFR-β/Cav-1 promotes breast cancer progression through autophagy regulation in CAFs, These findings provide a theoretical basis for potential therapeutic method for treating breast cancer.

摘要

背景

全球乳腺癌发病率一直在上升。癌症相关成纤维细胞（CAFs）是肿瘤微环境（TME）的关键基质成分，通过与癌细胞动态相互作用在肿瘤生长中发挥关键作用。自噬已在转移级联的多个阶段得到广泛研究。然而，两种关键膜蛋白，血小板衍生生长因子受体-β（PDGFR-β）和小窝蛋白-1（Cav-1），在调节CAFs自噬及其对癌细胞侵袭和迁移的影响方面仍不清楚。

方法

使用TCGA数据库分析PDGFR-β表达与乳腺癌患者临床特征之间的关联。在癌细胞中过表达或药理学抑制PDGFR-β。通过蛋白质免疫印迹和逆转录定量聚合酶链反应（RT-qPCR）分析自噬相关标志物和信号蛋白，同时对乳酸分泌和活性氧水平进行定量。通过伤口愈合和Transwell实验评估乳腺癌细胞的迁移和侵袭，并通过免疫荧光和免疫共沉淀（Co-IP）验证PDGFR-β/Cav1相互作用。采用乳腺癌小鼠模型评估体内肿瘤进展和自噬调节。

结果

该研究表明，PDGFR-β通过mTOR/FIP200/ATG13信号促进CAFs中的自噬。PDGFR-β/Cav-1通过自噬介导的代谢重编程增强CAFs中的糖酵解，导致乳酸输出增加，从而促进乳腺癌细胞生长。此外，CAFs自噬通过HIF-1α/MCT4/MCT1信号通路调节乳腺癌细胞的侵袭和迁移。这些发现表明，CAFs中PDGFR-β/Cav-1介导的自噬增强了乳腺癌细胞的侵袭、迁移和上皮-间质转化（EMT），共同突出了CAFs自噬在促进乳腺癌进展中的关键作用。