单细胞和单细胞核转录组分析揭示了高BMI乳腺癌患者肿瘤相关脂肪微环境中的动态细胞特征。

Single-Cell and Single-Nuclei transcriptomics profiling reveals dynamic cellular features in tumor-related adipose microenvironment of breast cancer patients with high BMI.

作者信息

Hu Xiaoxiao, Jia Fang, Li Lili, Chen Wuzhen, Zhang Leyi, Pan Jun, Zhu Sangsang, Wang Zhen, Huang Jian

机构信息

Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.

Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China; Department of Medical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang, China.

出版信息

Transl Oncol. 2025 Jul;57:102408. doi: 10.1016/j.tranon.2025.102408. Epub 2025 May 10.

DOI:10.1016/j.tranon.2025.102408

PMID:40344915

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12166941/

Abstract

OBJECTIVES

High body mass index (BMI), encompassing overweight and obesity, is a well-established risk factor for developing breast cancer (BC). The underlying mechanisms linking elevated BMI to increased BC risk involve metabolic reprogramming and chronic inflammatory microenvironments regulated by cellular networks within breast white adipose tissue (WAT). However, the complicated landscape and specific cell chat leading to BC-related adipose microenvironment remained unclear.

MATERIALS AND METHODS

We unveiled a comprehensive cell atlas by employing single-cell (N = 27) and single-nuclei (N = 6) transcriptomics to address dynamic changes of immune and stromal cell components within WAT in high BMI population. Bulk RNA-seq data sets were used for validation.

RESULTS

Characteristics of adipose-infiltrating tissue-resident macrophages (PVMs), APOD+γδ T cells, and mature FKBP5+ adipocytes in breast cancer women with high BMI were revealed, in terms of transcriptional genes, metabolism features, developmental trajectories and gene set enrichment analysis (GSEA). PVMs upregulated c-Maf combined with its co-activator CREB1 to increase TCA cycles. APOD+γδ T cells were found to elevate intracellular lipid metabolism, leading to poor clinical prognosis. Mature FKBP5+adipocytes served as an advanced adipogenesis mediator to promote tumor aggressiveness. In-depth analysis of cell-cell interactions uncovered a remodeling trend towards metabolic dysfunction and chronic inflammation in WAT with weight gain via EGF, CXCL, and CCL signalings.

CONCLUSION

These results provided a novel understanding of detailed and unbiased cellular landscape of WAT in breast cancer with high BMI from single-cell atlas perspective, uncovering interplays between breast adipose-infiltrating immune cells and stromal cells that promote progression of BC under high BMI conditions.

摘要

目的

高体重指数（BMI），包括超重和肥胖，是患乳腺癌（BC）的一个公认风险因素。将升高的BMI与BC风险增加联系起来的潜在机制涉及代谢重编程以及由乳腺白色脂肪组织（WAT）内的细胞网络调节的慢性炎症微环境。然而，导致BC相关脂肪微环境的复杂情况和特定细胞间通讯仍不清楚。

材料与方法

我们通过采用单细胞（N = 27）和单细胞核（N = 6）转录组学揭示了一个全面的细胞图谱，以解决高BMI人群WAT中免疫和基质细胞成分的动态变化。批量RNA测序数据集用于验证。

结果

从转录基因、代谢特征、发育轨迹和基因集富集分析（GSEA）方面揭示了高BMI乳腺癌女性中脂肪浸润组织驻留巨噬细胞（PVMs）、APOD+γδ T细胞和成熟FKBP5+脂肪细胞的特征。PVMs上调c-Maf及其共激活因子CREB1以增加三羧酸循环。发现APOD+γδ T细胞可提高细胞内脂质代谢，导致临床预后不良。成熟的FKBP5+脂肪细胞作为一种晚期脂肪生成介质，促进肿瘤侵袭性。对细胞间相互作用的深入分析发现，随着体重增加，WAT通过表皮生长因子（EGF）、CXC趋化因子（CXCL）和CC趋化因子（CCL）信号传导朝着代谢功能障碍和慢性炎症的重塑趋势。