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Stromal Gas6 promotes the progression of premalignant mammary cells

Oncogene volume 38, pages 2437–2450 (2019)Cite this article

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Abstract

Tumor progression is regulated by a complex interplay between neoplastic cells and the tumor microenvironment. Tumor-associated macrophages have been shown to promote breast cancer progression in advanced disease and more recently, in early stage cancers. However, little is known about the macrophage-derived factors that promote tumor progression in early stage lesions. Using a p53-null model of early stage mammary tumor progression, we found that Gas6 is highly expressed in pre-invasive lesions associated with increased infiltrating macrophages, as compared with those with few recruited macrophages. We show that F4/80+CD11b+ macrophages produce Gas6 in premalignant lesions in vivo, and that macrophage-derived Gas6 induces a tumor-like phenotype ex vivo. Using a 3-D co-culture system, we show that macrophage-derived Gas6 activates its receptor Axl and downstream survival signals including Akt and STAT3, which was accompanied by altered E-cadherin expression to induce a malignant morphology. In vivo studies demonstrated that deletion of stromal Gas6 delays early stage progression and decreases tumor formation, while tumor growth in established tumors remains unaffected. These studies suggest that macrophage-derived Gas6 is a critical regulator of the transition from premalignant to invasive cancer, and may lead to the development of unique biomarkers of neoplastic progression for patients with early stage breast cancer, including ductal carcinoma in situ.

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Acknowledgements

This work was supported by Susan G. Komen CCR16377665 (HLM), NIH R01 CA212518 (HLM), and the Tulane Cancer Center through the Cancer Crusaders of New Orleans. We would like to thank Dr. Dorota Wyczechowska from the LCRC Cell Immunology and Metabolism Core (NIH/NIGMS 1P30GM114732-01) for assistance with FACS and Dr. Leann Myers for help with statistical analysis. We would like to acknowledge Alexandra Giardina at the LCRC Biospecimen Core and Dr. Lyndsey Buckner Baiamonte, Jeannine Ascani, and Dr. Michelle Ponder at the Oschner Biorepository Unit for human DCIS tissues.

Author contributions

AMG: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing; ECC: conception and design, collection and assembly of data, data analysis and interpretation; KLM: collection and assembly of data; AMD: collection and assembly of data; ZG: collection and assembly of data; CRF: collection and assembly of data; MAL: collection and assembly of data; PC: collection of data and final approval of manuscript; FK: conception, design and final approval of manuscript; DM: conception and design, final approval of manuscript; HLM: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing, financial support.

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  1. These authors contributed equally: Angelica M. Gomes, Emily C. Carron.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane School of Medicine, New Orleans, LA, USA

    Angelica M. Gomes, Kylie L. Mills, Alexa M. Dow, Zane Gray, Christopher R. Fecca & Heather L. Machado

  2. Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA

    Emily C. Carron

  3. Ochsner Biorepository, Department of Research, Ochsner Clinic Foundation, New Orleans, LA, USA

    Meredith A. Lakey

  4. Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), Vesalius Research Center, VIB, Leuven, B-3000, Belgium

    Peter Carmeliet

  5. State Key Laboratory of Ophthalmology, Zhongsan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China

    Peter Carmeliet

  6. Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, B-3000, Belgium

    Peter Carmeliet

  7. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    Frances Kittrell & Daniel Medina

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Correspondence to Heather L. Machado.

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Gomes, A.M., Carron, E.C., Mills, K.L. et al. Stromal Gas6 promotes the progression of premalignant mammary cells. Oncogene 38, 2437–2450 (2019). https://doi.org/10.1038/s41388-018-0593-5

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