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Macrophage-mediated RON signaling supports breast cancer growth and progression through modulation of IL-35

Oncogene volume 41, pages 321–333 (2022)Cite this article

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Abstract

Tumor associated macrophages (TAMs) play a major role in regulating mammary tumor growth and in directing the responses of tumor infiltrating leukocytes in the microenvironment. However, macrophage-specific mechanisms regulating the interactions of macrophages with tumor cells and other leukocytes that support tumor progression have not been extensively studied. In this study, we show that the activation of the RON receptor tyrosine kinase signaling pathway specifically in macrophages supports breast cancer growth and metastasis. Using clinically relevant murine models of breast cancer, we demonstrate that loss of macrophage RON expression results in decreases in mammary tumor cell proliferation, survival, cancer stem cell self-renewal, and metastasis. Macrophage RON signaling modulates these phenotypes via direct effects on the tumor proper and indirectly by regulating leukocyte recruitment including macrophages, T-cells, and B-cells in the mammary tumor microenvironment. We further show that macrophage RON expression regulates the macrophage secretome including IL-35 and other immunosuppressive factors. Overall, our studies implicate activation of RON signaling in macrophages as a key player in supporting a thriving mammary pro-tumor microenvironment through novel mechanisms including the augmentation of tumor cell properties through IL-35.

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Fig. 1: Myeloid RON signaling sustains BCa growth and survival.
Fig. 2: RON signaling within myeloid cells promotes BCa cell metastasis and self-renewal.
Fig. 3: Macrophage-specific RON signaling sustains BCa growth and survival.
Fig. 4: Loss of RON signaling in macrophages alters macrophage functions to inhibit tumor cell proliferation, survival, migration, and self-renewal.
Fig. 5: RON signaling in macrophages alters the macrophage secretome to support immunomodulatory pathways and the production of IL-12 family members.
Fig. 6: Breast cancer patients with high RON and IL12A (p35) expression have poorer relapse-free survival and distant metastasis-free survival.

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Acknowledgements

We would like to thank Vidjaya L. Premkumar, Lennox Brooks, Rebekah Karns, James Davis, and Madison Nashu for their technical and bioinformatic assistance. US Department of Veterans Affairs research grant 1IOBX000803 (SEW); National Institutes of Health grants R01 CA239697 (SEW), T32 CA117846 (SEW, SJRT, NMB, JRB), F31 CA228373 (BGH, SEW), and National Institutes of Diabetes & Digestive & Kidney Diseases grant P30 DK078392.

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  1. These authors contributed equally: Sasha J. Ruiz-Torres, Jennifer R. Bourn.

Authors and Affiliations

  1. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267-0521, USA

    Sasha J. Ruiz-Torres, Jennifer R. Bourn, Nancy M. Benight, Brian G. Hunt, Carissa Lester & Susan E. Waltz

  2. Research Service, Cincinnati Veterans Affairs Medical Center, Cincinnati, OH, 45267, USA

    Susan E. Waltz

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The authors have made the following declarations about their contributions: Conceived and designed experiments: SJRT, JRB, BGH, and SEW. Performed experiments: SJRT, NMB, JRB, BGH, and CL. Analyzed data: SJRT, JRB, NMB, BGH, CL, and SEW. Wrote the paper: SJRT, JRB, BGH, and SEW.

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Correspondence to Susan E. Waltz.

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Ruiz-Torres, S.J., Bourn, J.R., Benight, N.M. et al. Macrophage-mediated RON signaling supports breast cancer growth and progression through modulation of IL-35. Oncogene 41, 321–333 (2022). https://doi.org/10.1038/s41388-021-02091-y

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