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    Single-cell RNA-seq reveals obesity-induced alterations in the brca1-mutated mammary gland microenvironment

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    Author
    Lo, Pang Kuo
    Yao, Yuan
    Zhou, Qun
    Date
    2020-08-10
    Journal
    Cancers
    Publisher
    MDPI AG
    Type
    Article
    
    Metadata
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    See at
    https://doi.org/10.3390/cancers12082235
    Abstract
    Clinical and experimental studies have shown that obesity increases the development and progression of breast cancer. The impact of obesity on the tumor microenvironment plays an important role in tumorigenesis, yet the precise mechanisms underlying obesity-mediated effects on cell-to-cell communication within the tumor microenvironment have been difficult to define. In this study, we conducted single-cell RNA sequencing (scRNA-seq) studies to investigate the impact of high-fat diet (HFD)-induced obesity on transcriptomic landscapes of stromal and immune cells in mammary glands of Brca1−/−;p53+/− mice, an animal breast cancer model. Hierarchical clustering and gene pathway enrichment analyses of scRNA-seq data showed that five different subtypes of stromal fibroblasts existed in mouse Brca1-mutated mammary glands. HFD-induced obesity led to upregulated expression of extracellular matrix (ECM) genes (Col3a1, Col6a3, Eln, and Sparc) and downregulated expression of immunoregulatory genes (Iigp1 and Cxcl10) in these stromal subtype cells. These findings, taken together, suggest that obesity alters the ECM composition and immune ecosystem through modulating the functionality of mammary stromal fibroblasts. Moreover, scRNA-seq analysis of mammary immune cells indicated that HFD-induced obesity promoted the generation and/or recruiting of pro-tumorigenic M2 macrophages in mammary glands. Our studies provide new insight into a mechanistic paradigm wherein obesity modulates the functions of stromal and immune cells to create the tumorigenic microenvironment for promoting breast tumorigenesis. © 2020 by the authors.
    Sponsors
    U.S. Department of Veterans Affairs
    Keyword
    Breast cancer
    High-fat diets
    Immune cells
    Obesity
    Single-cell RNA sequencing (scRNA-seq), microenvironment
    Stroma
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/13620
    ae974a485f413a2113503eed53cd6c53
    10.3390/cancers12082235
    Scopus Count
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