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E2f3 in tumor macrophages promotes lung metastasis

Oncogene volume 35, pages 3636–3646 (2016)Cite this article

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Abstract

The Rb-E2F axis is an important pathway involved in cell-cycle control that is deregulated in a number of cancers. E2f transcription factors have distinct roles in the control of cell proliferation, cell survival and differentiation in a variety of tissues. We have previously shown that E2fs are important downstream targets of a CSF-1 signaling cascade involved in myeloid development. In cancer, tumor-associated macrophages (TAMs) are recruited to the tumor stroma in response to cytokines secreted by tumor cells, and are believed to facilitate tumor cell invasion and metastasis. Using the MMTV-Polyoma Middle T antigen (PyMT) mouse model of human ductal carcinoma, we show that the specific ablation of E2f3 in TAMs, but not in tumor epithelial cells, attenuates lung metastasis without affecting primary tumor growth. Histological analysis and gene expression profiling suggest that E2f3 does not impact the proliferation or survival of TAMs, but rather controls a novel gene expression signature associated with cytoskeleton rearrangements, cell migration and adhesion. This E2f3 TAM gene expression signature was sufficient to predict cancer recurrence and overall survival of estrogen receptor (ER)-positive breast cancer patients. Interestingly, we find that E2f3b but not E2f3a levels are elevated in TAMs from PyMT mammary glands relative to controls, suggesting a differential role for these isoforms in metastasis. In summary, these findings identify E2f3 as a key transcription factor in TAMs, which influences the tumor microenvironment and tumor cell metastasis.

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Acknowledgements

We thank Bryan Mcelwain for technical assistance with flow cytometry. This work was funded by NIH grants R01CA121275, R01CA098956 and P01CA097189 MC and GL to GL. PT and NS are recipients of the T32 fellowship (CA 106196-06).

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Authors and Affiliations

  1. Human Cancer Genetics Program, The Ohio State University,, Columbus,, OH, USA

    P Trikha, N Sharma, C Pena, A Reyes, T Pécot, S Khurshid, M Rawahneh, J Moffitt, M C Ostrowski & G Leone

  2. Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine and Public Health, The Ohio State University, Columbus,, OH, USA

    P Trikha, N Sharma, C Pena, A Reyes, T Pécot, S Khurshid, M Rawahneh, J Moffitt, M C Ostrowski & G Leone

  3. Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus,, OH, USA

    P Trikha, N Sharma, C Pena, A Reyes, T Pécot, S Khurshid, M Rawahneh, J Moffitt, M C Ostrowski & G Leone

  4. Center for Biostatistics, College of Medicine, The Ohio State University,, Columbus,, OH, USA

    J A Stephens & S A Fernandez

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Correspondence to G Leone.

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Trikha, P., Sharma, N., Pena, C. et al. E2f3 in tumor macrophages promotes lung metastasis. Oncogene 35, 3636–3646 (2016). https://doi.org/10.1038/onc.2015.429

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