ORIGINAL RESEARCH article
Front. Oncol.
Sec. Breast Cancer
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1619171
This article is part of the Research TopicExploring the Breast Tumor Microenvironment: Association to Metastasis, Novel Risk Factors and Novel Treatments and Immunotherapies: Volume II.View all 9 articles
SPOCK1 promotes the progression of breast cancer by modulating cancer-associated fibroblasts and exerts a synergistic effect with ANXA2
Provisionally accepted
- 1Tianjin First Central Hospital, Tianjin, China
- 2Tianjin Haihe Hospital, Tianjin, China
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SPOCK1, a matricellular glycoprotein, has been implicated in tumor progression, metastasis, and the tumor immune microenvironment, yet its specific roles in breast cancer (BRCA) remain unclear. This study aimed to systematically explore the expression pattern, prognostic significance, mutation landscape, immune association, and spatial localization of SPOCK1 in breast cancer through integrated multi-omics analyses.Transcriptomic, genomic, and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were utilized. Bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) analyses were conducted, including functional enrichment, immune infiltration assessments, mutation profiling, and transcription factor activity analysis. Multiplex immunohistochemistry (mIHC) was performed to validate the spatial distribution of SPOCK1+ cancer-associated fibroblasts (CAFs) within the tumor microenvironment. Statistical analyses were performed using R and GraphPad Prism.SPOCK1 was broadly overexpressed in multiple cancer types and significantly associated with poor prognosis in BRCA. High SPOCK1 expression correlated with immune checkpoint activation, enhanced immune infiltration, and enriched metastasis-related pathways such as epithelialmesenchymal transition (EMT) and TGF-β signaling. Single-cell analysis identified CAFs as the primary cell population expressing SPOCK1, with spatial mIHC confirming their close proximity to tumor cells. Furthermore, SPOCK1-high CAFs exhibited stronger intercellular communications with malignant cells via collagen, fibronectin, and IGFBP signaling pathways, alongside distinct transcription factor and metabolic profiles. In breast cancer CAF cell lines with knockdown of ANXA2 we found that the expression of both SPOCK1 and IGF1 was reduced.SPOCK1 serves as a critical regulator of breast cancer progression, influencing tumor metastasis and reshaping the immune microenvironment via CAF-mediated mechanisms. These findings suggest that targeting SPOCK1+ CAFs could offer new therapeutic opportunities for breast cancer treatment.
Keywords: SPOCK1, breast cancer, AnxA2, Tumor Microenvironment, Cancer-associated fibroblasts 1.Introduction
Received: 27 Apr 2025; Accepted: 26 Jun 2025.
Copyright: © 2025 Yuan, Fei and Fan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Jie Yuan, Tianjin First Central Hospital, Tianjin, China
Meng Fan, Tianjin First Central Hospital, Tianjin, China
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