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<p>Primary breast cancer (BC) and metastatic tumors exhibit distinct tumor microenvironment (TME) ecosystems, and the heterogeneity of the TME of BC poses challenges to effective therapies. Evaluating the TME at the single-cell and spatial profiles offers potential for more precise treatments. However, due to the challenge of obtaining surgical specimens of both primary BC and oligo-recurrent lung metastasis simultaneously for high-resolution spatial analysis, the TME of lung-specific metastases using paired samples remains largely unexplored. In this study, we developed a comprehensive strategy using imaging mass cytometry (IMC), spatial proteomics, single-nucleus RNA-seq (snRNA-seq) and multiplex immunofluorescence to explore the spatial topology of lung-specific metastasis and the underlying biological mechanisms based on formalin-fixed paraffin-embedded (FFPE) samples from BC and paired lung metastasis. A total of 250,600 high-quality cells with spatial information revealed by IMC depicted the spatial differences in the TME between BC and lung metastasis. A significant increase in HLA-DR<sup>+</sup> epithelial cells, endothelial cells and exhausted T cells was detected in lung metastases compared to primary sites, with this difference accentuated in the triple-negative subtype. Moreover, a distinct cellular hub comprising endothelial cells and HLA-DR<sup>+</sup> epithelial cells implies the potential promising effect of anti-angiogenic therapy and immunotherapy in BC with lung metastasis, which was further validated by multiplex immunofluorescence analysis. Spatial proteomics further explored the underlying mechanism of TME components identified by IMC analysis. snRNA-seq validated the enrichment of endothelial cells in lung metastasis than that in BC at a whole FFPE slide level. In conclusion, this study determines the spatial multi-omics profiling of TME components at a single-cell resolution using paired samples of primary BC and lung oligo-metastasis. The comprehensive analysis may contribute to the development of therapeutic options.</p><p></p>

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Spatial multi-omics profiling of breast cancer oligo-recurrent lung metastasis

  • 期刊论文

  • 发表日期：

    2025年4月15日

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  • Yang Gao,
  • Bin Li,
  • Yuzhi Jin,
  • Jinlin Cheng,
  • Weihong Tian,
  • Lixiong Ying,
  • Libing Hong,
  • Shan Xin,
  • Bo Lin,
  • Chuan Liu,
  • Xuqi Sun,
  • Jun Zhang,
  • Haibo Zhang,
  • Jindong Xie,
  • Xinpei Deng,
  • Xiaomeng Dai,
  • Lulu Liu,
  • Yi Zheng,
  • Peng Zhao,
  • Guangchuan Yu,
  • Weijia Fang,
  • Xuanwen Bao

摘要

Primary breast cancer (BC) and metastatic tumors exhibit distinct tumor microenvironment (TME) ecosystems, and the heterogeneity of the TME of BC poses challenges to effective therapies. Evaluating the TME at the single-cell and spatial profiles offers potential for more precise treatments. However, due to the challenge of obtaining surgical specimens of both primary BC and oligo-recurrent lung metastasis simultaneously for high-resolution spatial analysis, the TME of lung-specific metastases using paired samples remains largely unexplored. In this study, we developed a comprehensive strategy using imaging mass cytometry (IMC), spatial proteomics, single-nucleus RNA-seq (snRNA-seq) and multiplex immunofluorescence to explore the spatial topology of lung-specific metastasis and the underlying biological mechanisms based on formalin-fixed paraffin-embedded (FFPE) samples from BC and paired lung metastasis. A total of 250,600 high-quality cells with spatial information revealed by IMC depicted the spatial differences in the TME between BC and lung metastasis. A significant increase in HLA-DR+ epithelial cells, endothelial cells and exhausted T cells was detected in lung metastases compared to primary sites, with this difference accentuated in the triple-negative subtype. Moreover, a distinct cellular hub comprising endothelial cells and HLA-DR+ epithelial cells implies the potential promising effect of anti-angiogenic therapy and immunotherapy in BC with lung metastasis, which was further validated by multiplex immunofluorescence analysis. Spatial proteomics further explored the underlying mechanism of TME components identified by IMC analysis. snRNA-seq validated the enrichment of endothelial cells in lung metastasis than that in BC at a whole FFPE slide level. In conclusion, this study determines the spatial multi-omics profiling of TME components at a single-cell resolution using paired samples of primary BC and lung oligo-metastasis. The comprehensive analysis may contribute to the development of therapeutic options.