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Oncogenic mTOR signalling recruits myeloid-derived suppressor cells to promote tumour initiation

Nature Cell Biology volume 18, pages 632644 (2016) | Download Citation

  • An Erratum to this article was published on 28 June 2016

This article has been updated

Abstract

Myeloid-derived suppressor cells (MDSCs) play critical roles in primary and metastatic cancer progression. MDSC regulation is widely variable even among patients harbouring the same type of malignancy, and the mechanisms governing such heterogeneity are largely unknown. Here, integrating human tumour genomics and syngeneic mammary tumour models, we demonstrate that mTOR signalling in cancer cells dictates a mammary tumour’s ability to stimulate MDSC accumulation through regulating G-CSF. Inhibiting this pathway or its activators (for example, FGFR) impairs tumour progression, which is partially rescued by restoring MDSCs or G-CSF. Tumour-initiating cells (TICs) exhibit elevated G-CSF. MDSCs reciprocally increase TIC frequency through activating Notch in tumour cells, forming a feedforward loop. Analyses of primary breast cancers and patient-derived xenografts corroborate these mechanisms in patients. These findings establish a non-canonical oncogenic role of mTOR signalling in recruiting pro-tumorigenic MDSCs and show how defined cancer subsets may evolve to promote and depend on a distinct immune microenvironment.

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  • 20 May 2016

    In the version of this Article originally published, in the fourth affiliation, 'Los Angeles' should have read 'Louisiana'. This has been corrected in all online versions of the Article.

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Acknowledgements

We would like to thank Novartis for providing BGJ-398, and H. C. Lo and D. Weiss for helpful input. We also thank the Antibody-Based Proteomics Shared Resource of the Dan L. Duncan Cancer Center supported by Cancer Center Support grant NCI P30CA125123, and A. Welm, Huntsman Cancer Institute, USA for generously providing some of the PDX models. X.H.-F.Z. is supported by NCI CA183878, the Breast Cancer Research Foundation, US Department of Defense DAMD W81XWH-13-1-0195, Susan G. Komen CCR14298445, and McNair Medical Institute. T.Welte is supported by the Helis Foundation. H.W. is supported by US Department of Defense DAMD W81XWH-13-1-0296. Studies with the p53-null tumours were supported by NIH grant CA148761 to J.M.R. and with the WNT1–iFGFR tumours by NIH grant CA16303 to J.M.R. RRPA experiments were supported by Cancer Prevention and Research Institute of Texas (CPRIT) Core Facilities Support Award RP120092 to D.P.E. The authors acknowledge the joint participation by Diana Helis Henry Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with Baylor College of Medicine.

Author information

Author notes

    • Jason I. Herschkowitz

    Present address: Cancer Research Center, University of Albany, 1400 Washington Avenue, Albany, New York 12222, USA.

Affiliations

  1. Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA

    • Thomas Welte
    • , Ik Sun Kim
    • , Lin Tian
    • , Xia Gao
    • , Hai Wang
    • , June Li
    • , Jason I. Herschkowitz
    • , Adam Pond
    • , Lacey E. Dobrolecki
    • , Yi Li
    • , Michael T. Lewis
    •  & Xiang H.-F. Zhang
  2. Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA

    • Thomas Welte
    • , Ik Sun Kim
    • , Lin Tian
    • , Xia Gao
    • , Hai Wang
    • , June Li
    • , Xue B. Holdman
    • , Jason I. Herschkowitz
    • , Adam Pond
    • , Lacey E. Dobrolecki
    • , Qianxing Mo
    • , Dean P. Edwards
    • , Shixia Huang
    • , Li Xin
    • , Jianming Xu
    • , Yi Li
    • , Michael T. Lewis
    • , Jeffrey M. Rosen
    •  & Xiang H.-F. Zhang
  3. Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA

    • Thomas Welte
    • , Ik Sun Kim
    • , Lin Tian
    • , Xia Gao
    • , Hai Wang
    • , June Li
    • , Xue B. Holdman
    • , Jason I. Herschkowitz
    • , Adam Pond
    • , Sarah Kurley
    • , Tuan Nguyen
    • , Lan Liao
    • , Lacey E. Dobrolecki
    • , Dean P. Edwards
    • , Shixia Huang
    • , Li Xin
    • , Jianming Xu
    • , Yi Li
    • , Michael T. Lewis
    • , Jeffrey M. Rosen
    •  & Xiang H.-F. Zhang
  4. Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana 70130, USA

    • Thomas Welte
  5. Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA

    • Ik Sun Kim
  6. Verna & Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA

    • Lin Tian
    •  & Thomas F. Westbrook
  7. Department of Microbiology & Immunology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555, USA

    • Guorui Xie
    • , Lan Pang
    •  & Tian Wang
  8. Department of Pathology and Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA

    • Qianxing Mo
    •  & Dean P. Edwards
  9. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA

    • Thomas F. Westbrook
  10. McNair Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA

    • Xiang H.-F. Zhang

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Contributions

Conception and design: X.H.-F.Z., J.M.R. and T.Welte. Development of methodology: T.Welte, I.S.K., L.T., X.G., S.H., J.X., T.Wang and Q.M. Acquisition of data: T.Welte, I.S.K., L.T., X.G., H.W., J.L., X.B.H., J.I.H., A.P., G.X., S.K., T.N., L.L., D.P.E., S.H., J.X., Y.L., M.T.L., T.Wang, T.F.W. and L.X. Analysis and interpretation of data: T.Welte, X.H.-F.Z., J.M.R., T.Wang, I.S.K. and Q.M. Writing and review of manuscript: X.H.-F.Z., T.Welte, T.Wang and J.M.R. Study supervision: X.H.-F.Z. and J.M.R.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jeffrey M. Rosen or Xiang H.-F. Zhang.

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https://doi.org/10.1038/ncb3355

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