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

Thomas Welte, Ik Sun Kim, Lin Tian, Xia Gao, Hai Wang, June Li, Xue B. Holdman, Jason I. Herschkowitz, Adam Pond, Guorui Xie, Sarah Kurley, Tuan Nguyen, Lan Liao, Lacey E. Dobrolecki, Lan Pang, Qianxing Mo, Dean P. Edwards, Shixia Huang, Li Xin, Jianming Xu & 6 others Yi Li, Michael T. Lewis, Tian Wang, Thomas F. Westbrook, Jeffrey M. Rosen, Xiang H F Zhang

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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.

Original languageEnglish (US)
Pages (from-to)632-644
Number of pages13
JournalNature Cell Biology
Volume18
Issue number6
DOIs
StatePublished - Jun 1 2016

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Granulocyte Colony-Stimulating Factor
Neoplasms
Neoplastic Stem Cells
Breast Neoplasms
Genomics
Myeloid-Derived Suppressor Cells
Heterografts

ASJC Scopus subject areas

  • Cell Biology

Cite this

Welte, T., Kim, I. S., Tian, L., Gao, X., Wang, H., Li, J., ... Zhang, X. H. F. (2016). Oncogenic mTOR signalling recruits myeloid-derived suppressor cells to promote tumour initiation. Nature Cell Biology, 18(6), 632-644. https://doi.org/10.1038/ncb3355

Oncogenic mTOR signalling recruits myeloid-derived suppressor cells to promote tumour initiation. / Welte, Thomas; Kim, Ik Sun; Tian, Lin; Gao, Xia; Wang, Hai; Li, June; Holdman, Xue B.; Herschkowitz, Jason I.; Pond, Adam; Xie, Guorui; Kurley, Sarah; Nguyen, Tuan; Liao, Lan; Dobrolecki, Lacey E.; Pang, Lan; Mo, Qianxing; Edwards, Dean P.; Huang, Shixia; Xin, Li; Xu, Jianming; Li, Yi; Lewis, Michael T.; Wang, Tian; Westbrook, Thomas F.; Rosen, Jeffrey M.; Zhang, Xiang H F.

In: Nature Cell Biology, Vol. 18, No. 6, 01.06.2016, p. 632-644.

Research output: Contribution to journalArticle

Welte, T, Kim, IS, Tian, L, Gao, X, Wang, H, Li, J, Holdman, XB, Herschkowitz, JI, Pond, A, Xie, G, Kurley, S, Nguyen, T, Liao, L, Dobrolecki, LE, Pang, L, Mo, Q, Edwards, DP, Huang, S, Xin, L, Xu, J, Li, Y, Lewis, MT, Wang, T, Westbrook, TF, Rosen, JM & Zhang, XHF 2016, 'Oncogenic mTOR signalling recruits myeloid-derived suppressor cells to promote tumour initiation', Nature Cell Biology, vol. 18, no. 6, pp. 632-644. https://doi.org/10.1038/ncb3355
Welte, Thomas ; Kim, Ik Sun ; Tian, Lin ; Gao, Xia ; Wang, Hai ; Li, June ; Holdman, Xue B. ; Herschkowitz, Jason I. ; Pond, Adam ; Xie, Guorui ; Kurley, Sarah ; Nguyen, Tuan ; Liao, Lan ; Dobrolecki, Lacey E. ; Pang, Lan ; Mo, Qianxing ; Edwards, Dean P. ; Huang, Shixia ; Xin, Li ; Xu, Jianming ; Li, Yi ; Lewis, Michael T. ; Wang, Tian ; Westbrook, Thomas F. ; Rosen, Jeffrey M. ; Zhang, Xiang H F. / Oncogenic mTOR signalling recruits myeloid-derived suppressor cells to promote tumour initiation. In: Nature Cell Biology. 2016 ; Vol. 18, No. 6. pp. 632-644.
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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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AU - Xu, Jianming

AU - Li, Yi

AU - Lewis, Michael T.

AU - Wang, Tian

AU - Westbrook, Thomas F.

AU - Rosen, Jeffrey M.

AU - Zhang, Xiang H F

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