Adipocyte mesenchymal transition contributes to mammary tumor progression

Qingzhang Zhu, Yi Zhu, Chelsea Hepler, Qianbin Zhang, Jiyoung Park, Christy Gliniak, Gervaise H. Henry, Clair Crewe, Dawei Bu, Zhuzhen Zhang, Shangang Zhao, Thomas Morley, Na Li, Dae Seok Kim, Douglas Strand, Yingfeng Deng, Jacob J. Robino, Oleg Varlamov, Ruth Gordillo, Mikhail G. KoloninChristine M. Kusminski, Rana K. Gupta, Philipp E. Scherer

    Research output: Contribution to journalArticlepeer-review

    1 Scopus citations

    Abstract

    Obesity is associated with increased cancer incidence and progression. However, the relationship between adiposity and cancer remains poorly understood at the mechanistic level. Here, we report that adipocytes from tumor-invasive mammary fat undergo de-differentiation to fibroblast-like precursor cells during tumor progression and integrate into the tumor microenvironment. Single-cell sequencing reveals that these de-differentiated adipocytes lose their original identities and transform into multiple cell types, including myofibroblast- and macrophage-like cells, with their characteristic features involved in immune response, inflammation, and extracellular matrix remodeling. The de-differentiated cells are metabolically distinct from tumor-associated fibroblasts but exhibit comparable effects on tumor cell proliferation. Inducing de-differentiation by Xbp1s overexpression promotes tumor progression despite lower adiposity. In contrast, promoting lipid-storage capacity in adipocytes through MitoNEET overexpression curbs tumor growth despite greater adiposity. Collectively, the metabolic interplay between tumor cells and adipocytes induces adipocyte mesenchymal transition and contributes to reconfigure the stroma into a more tumor-friendly microenvironment.

    Original languageEnglish (US)
    Article number111362
    JournalCell Reports
    Volume40
    Issue number11
    DOIs
    StatePublished - Sep 13 2022

    Keywords

    • CP: Cancer
    • CP: Metabolism
    • adipocyte
    • breast cancer
    • de-differentiation
    • obesity

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)

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