STAT5 is activated in macrophages by breast cancer cell-derived factors and regulates macrophage function in the tumor microenvironment

Emily A. Jesser, Nicholas J. Brady, Danielle N Huggins, Patrice M Witschen, Christine H. O’Connor, Kathryn L. Schwertfeger

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Background: In breast cancer, complex interactions between tumor cells and cells within the surrounding stroma, such as macrophages, are critical for tumor growth, progression, and therapeutic response. Recent studies have highlighted the complex nature and heterogeneous populations of macrophages associated with both tumor-promoting and tumor-inhibiting phenotypes. Defining the pathways that drive macrophage function is important for understanding their complex phenotypes within the tumor microenvironment. Signal transducer and activator of transcription (STAT) transcription factors, such as STAT5, are key regulators of immune cell function. The studies described here investigate the functional contributions of STAT5 to tumor-associated macrophage function in breast cancer. Methods: Initial studies were performed using a panel of human breast cancer and mouse mammary tumor cell lines to determine the ability of tumor cell-derived factors to induce STAT5 activation in macrophages. Further studies used these models to identify soluble factors that activate STAT5 in macrophages. To delineate STAT5-specific contributions to macrophage function, a conditional model of myeloid STAT5 deletion was used for in vitro, RNA-sequencing, and in vivo studies. The effects of STAT5 deletion in macrophages on tumor cell migration and metastasis were evaluated using in vitro co-culture migration assays and an in vivo tumor cell-macrophage co-injection model. Results: We demonstrate here that STAT5 is robustly activated in macrophages by tumor cell-derived factors and that GM-CSF is a key cytokine stimulating this pathway. The analysis of RNA-seq studies reveals that STAT5 promotes expression of immune stimulatory genes in macrophages and that loss of STAT5 in macrophages results in increased expression of tissue remodeling factors. Finally, we demonstrate that loss of STAT5 in macrophages promotes tumor cell migration in vitro and mammary tumor metastasis in vivo. Conclusions: Breast cancer cells produce soluble factors, such as GM-CSF, that activate the STAT5 pathway in macrophages and drive expression of inflammatory factors. STAT5 deletion in myeloid cells enhances metastasis, suggesting that STAT5 activation in tumor-associated macrophages protects against tumor progression. Understanding mechanisms that drive macrophage function in the tumor microenvironment will ultimately lead to new approaches that suppress tumor-promoting functions while enhancing their anti-tumor functions.

Original languageEnglish (US)
Article number104
JournalBreast Cancer Research
Volume23
Issue number1
DOIs
StatePublished - Dec 2021

Bibliographical note

Funding Information:
Research reported in this publication was supported by NIH/National Cancer Institute F31CA220746 to EAJ; American Cancer Society North Region Research Council Post-doctoral Fellowship PF-18-140-01-CSM to DNH; NIH funding T32OD010993 to PMW. NIH funding R01CA215052, R01HD095858 and R21CA235385 and DOD funding BC191153 to KLS. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
The authors thank Dr. Jeffrey Rosen (Baylor College of Medicine), Dr. Thomas Griffith and Dr. Michael Farrar (University of Minnesota) for providing reagents. The authors would also like to thank Dr. Andrew Nelson for advice and guidance in quantifying lung metastasis.

Publisher Copyright:
© 2021, The Author(s).

Keywords

  • Breast cancer
  • Metastasis
  • STAT5
  • Tumor microenvironment
  • Tumor-associated macrophages

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