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机器学习分析揭示了乳腺癌中的肿瘤异质性和基质-免疫微环境。

Machine learning analysis reveals tumor heterogeneity and stromal-immune niches in breast cancer.

作者信息

Kuang Junjie, Zhong Guofang, Zhao Linfeng, Yuan Xia, Zhou Yundong, Li Jun

机构信息

Cancer Center, Huizhou First Hospital, Huizhou, Guangdong, China.

The Second Department of Cancer Center, Huizhou First Hospital, Huizhou, Guangdong, China.

出版信息

NPJ Digit Med. 2025 Sep 2;8(1):565. doi: 10.1038/s41746-025-01967-7.

DOI:10.1038/s41746-025-01967-7
PMID:40897851
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405446/
Abstract

Breast cancer is a leading cause of cancer-related mortality, with tumor heterogeneity and drug resistance posing significant challenges to treatment. We integrated single-cell RNA sequencing, spatial transcriptomics, and bulk RNA-seq deconvolution to analyze BRCA samples. Our analysis identified 15 major cell clusters, including neoplastic epithelial, immune, stromal, and endothelial populations. Notably, low-grade tumors showed enriched subtypes, such as CXCR4+ fibroblasts, IGKC+ myeloid cells, and CLU+ endothelial cells, with distinct spatial localization and immune-modulatory functions. These subtypes were paradoxically linked to reduced immunotherapy responsiveness, despite their association with favorable clinical features. High-grade tumors exhibited reprogrammed intercellular communication, with expanded MDK and Galectin signaling. Bulk RNA-seq deconvolution further supported the prognostic significance of low-grade-enriched subtypes. Our findings highlight the heterogeneity of the tumor microenvironment and provide new insights into immune evasion and therapeutic resistance in breast cancer.

摘要

乳腺癌是癌症相关死亡的主要原因，肿瘤异质性和耐药性给治疗带来了重大挑战。我们整合了单细胞RNA测序、空间转录组学和批量RNA-seq反卷积分析来分析乳腺癌样本。我们的分析确定了15个主要细胞簇，包括肿瘤上皮细胞、免疫细胞、基质细胞和内皮细胞群体。值得注意的是，低级别肿瘤显示出富集的亚型，如CXCR4+成纤维细胞、IGKC+髓样细胞和CLU+内皮细胞，具有独特的空间定位和免疫调节功能。尽管这些亚型与良好的临床特征相关，但矛盾的是，它们与免疫治疗反应性降低有关。高级别肿瘤表现出细胞间通讯重编程，MDK和半乳糖凝集素信号传导增强。批量RNA-seq反卷积进一步支持了低级别富集亚型的预后意义。我们的研究结果突出了肿瘤微环境的异质性，并为乳腺癌的免疫逃逸和治疗耐药性提供了新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62f3/12405446/4dfdcd815912/41746_2025_1967_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62f3/12405446/61e3b84b8ebb/41746_2025_1967_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62f3/12405446/1f7d5184c823/41746_2025_1967_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62f3/12405446/116ca73eeef9/41746_2025_1967_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62f3/12405446/762fb62577fe/41746_2025_1967_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62f3/12405446/d5d19cc69c7e/41746_2025_1967_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62f3/12405446/d006df1bd985/41746_2025_1967_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62f3/12405446/c77e488fa9da/41746_2025_1967_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62f3/12405446/4dfdcd815912/41746_2025_1967_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62f3/12405446/61e3b84b8ebb/41746_2025_1967_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62f3/12405446/1f7d5184c823/41746_2025_1967_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62f3/12405446/116ca73eeef9/41746_2025_1967_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62f3/12405446/762fb62577fe/41746_2025_1967_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62f3/12405446/d5d19cc69c7e/41746_2025_1967_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62f3/12405446/d006df1bd985/41746_2025_1967_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62f3/12405446/c77e488fa9da/41746_2025_1967_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62f3/12405446/4dfdcd815912/41746_2025_1967_Fig8_HTML.jpg

相似文献

[1]
Machine learning analysis reveals tumor heterogeneity and stromal-immune niches in breast cancer.

NPJ Digit Med. 2025-9-2

[2]
Deciphering the tumor immune microenvironment: single-cell and spatial transcriptomic insights into cervical cancer fibroblasts.

J Exp Clin Cancer Res. 2025-7-5

[3]
Systematic screening of metabolic pathways to identify two breast cancer subtypes with divergent immune characteristics.

Sci Rep. 2025-7-1

[4]
Single-cell and spatial transcriptomics profile the interaction of macrophages and fibroblasts in non-small cell lung cancer.

Transl Lung Cancer Res. 2025-7-31

[5]
Multi-pronged analysis of pediatric low-grade glioma reveals a unique tumor microenvironment associated with BRAF alterations.

bioRxiv. 2024-4-10

[6]
Multi-omics analysis reveals the role of ribosome biogenesis in malignant clear cell renal cell carcinoma and the development of a machine learning-based prognostic model.

Front Immunol. 2025-6-26

[7]
Integrated single-cell and transcriptomic analysis of bone marrow-derived metastatic neuroblastoma reveals molecular mechanisms of metabolic reprogramming.

Sci Rep. 2025-8-5

[8]
The role of collagen type VI alpha 6 chain as a potential tumor suppressor in breast cancer: an immune regulation perspective.

BMC Cancer. 2025-8-23

[9]
Integrated multiomics analysis identifies PHLDA1+ fibroblasts as prognostic biomarkers and mediators of biological functions in pancreatic cancer.

Front Immunol. 2025-7-4

[10]
Novel multi-omics analysis revealing metabolic heterogeneity of breast cancer cell and subsequent development of associated prognostic signature.

Transl Oncol. 2025-9

本文引用的文献

[1]
Lectin-like Transcript-1 (LLT1) Expression in Oral Squamous Cell Carcinomas: Prognostic Significance and Relationship with the Tumor Immune Microenvironment.

Int J Mol Sci. 2024-4-13

[2]
Single-cell transcriptomics reveal distinct immune-infiltrating phenotypes and macrophage-tumor interaction axes among different lineages of pituitary neuroendocrine tumors.

Genome Med. 2024-4-24

[3]
The homeoprotein HOXB2 limits triple-negative breast carcinogenesis via extracellular matrix remodeling.

Int J Biol Sci. 2024

[4]
Epigenetic modulation of antitumor immunity and immunotherapy response in breast cancer: biological mechanisms and clinical implications.

Front Immunol. 2023

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Cancer statistics, 2024.

CA Cancer J Clin. 2024

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Breast cancer organoids derived from patients: A platform for tailored drug screening.

Biochem Pharmacol. 2023-11

[7]
The emerging role of fatty acid binding protein 5 (FABP5) in cancers.

Drug Discov Today. 2023-7

[8]
Epidemiology, clinical outcomes, and unmet needs of patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases: A systematic literature review.

Cancer Treat Rev. 2023-4

[9]
Molecular Profiling in Early ER + Breast Cancer to Aid Systemic Therapy Decisions.

Curr Oncol Rep. 2023-5

[10]
Epigenetic remodeling of the immune landscape in cancer: therapeutic hurdles and opportunities.

J Biomed Sci. 2023-1-10

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