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A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages

Nature Cell Biology volume 16, pages 11051117 (2014) | Download Citation

  • An Addendum to this article was published on 27 November 2015

Abstract

The cell-biological program termed the epithelial–mesenchymal transition (EMT) confers on cancer cells mesenchymal traits and an ability to enter the cancer stem cell (CSC) state. However, the interactions between CSCs and their surrounding microenvironment are poorly understood. Here we show that tumour-associated monocytes and macrophages (TAMs) create a CSC niche through juxtacrine signalling with CSCs. We performed quantitative proteomic profiling and found that the EMT program upregulates the expression of CD90, also known as Thy1, and EphA4, which mediate the physical interactions of CSCs with TAMs by directly binding with their respective counter-receptors on these cells. In response, the EphA4 receptor on the carcinoma cells activates Src and NF-κB. In turn, NF-κB in the CSCs induces the secretion of a variety of cytokines that serve to sustain the stem cell state. Indeed, admixed macrophages enhance the CSC activities of carcinoma cells. These findings underscore the significance of TAMs as important components of the CSC niche.

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Acknowledgements

We thank L. Ma and T. Shibue for critical reviews of the manuscript, R. Bronson for evaluating the histopathology, D. R. Mani and P. Thiru for statistical analyses and C. Baty for assistance in imaging. We also thank A. Oberle, J. Karlsson and E. Procopio for technical assistance. This research was supported by the MIT Ludwig Center for Molecular Oncology and by grants from the Breast Cancer Research Foundation and National Institutes of Health (NIH; R01-CA078461, P01-CA080111 and U54-CA163109) to R.A.W. Additional support comes in part from the Department of Defense (BC032981 and BC044784), NIH (P30CA047904), the Hillman Foundation and the Glimmer of Hope Foundation to V.S.D. This work was also supported in part by the Broad Institute of MIT and Harvard, and by grants from NIH (U24CA160034) to S.A.C. R.A.W. is an American Cancer Society and D. K. Ludwig Foundation Cancer Research Professor. Postdoctoral fellowship support for H.L. was from the Cancer Research Institute (New York) and the MIT Ludwig Center for Molecular Oncology.

Author information

Affiliations

  1. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA

    • Haihui Lu
    • , Wai Leong Tam
    • , Julia Fröse
    • , Xin Ye
    • , Elinor Ng Eaton
    • , Ferenc Reinhardt
    •  & Robert A. Weinberg
  2. MIT Ludwig Center for Molecular Oncology, Cambridge, Massachusetts 02139, USA

    • Haihui Lu
    • , Wai Leong Tam
    •  & Robert A. Weinberg
  3. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA

    • Karl R. Clauser
    •  & Steven A. Carr
  4. Genome Institute of Singapore, 60 Biopolis Street Singapore 138672, Singapore

    • Wai Leong Tam
  5. German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

    • Julia Fröse
  6. University of Heidelberg, 69120 Heidelberg, Germany

    • Julia Fröse
  7. Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA

    • Vera S. Donnenberg
  8. Department of Cardiothoracic Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15213, USA

    • Vera S. Donnenberg
  9. Magee-Womens Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15213, USA

    • Rohit Bhargava
  10. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA

    • Robert A. Weinberg

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Contributions

H.L. designed the project, conducted experiments and analysed data under the guidance of R.A.W. K.R.C. and S.A.C. performed the proteomics profiling and data analysis. V.S.D. and R.B. performed patient sample staining, imaging and quantification. W.L.T. performed gene microarray, chromatin immunoprecipitation and data analysis. H.L. and X.Y. performed immunofluorescence and imaging of mouse tumour tissues. J.F. contributed to signalling pathway analysis and E.N.E. provided technical expertise. F.R. performed mouse surgeries. H.L. and R.A.W. wrote the manuscript. All authors critically read and contributed to the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Robert A. Weinberg.

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DOI

https://doi.org/10.1038/ncb3041

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