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Nat Cell Biol. 2019 Jul;21(7):879-888. doi: 10.1038/s41556-019-0346-x. Epub 2019 Jul 1.

Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments.

Janiszewska M1,2,3,4, Tabassum DP1,5, Castaño Z3,6, Cristea S7,8,9, Yamamoto KN7,8,9, Kingston NL1, Murphy KC1, Shu S1,2,3, Harper NW1, Del Alcazar CG1,2,3, Alečković M1,2,3, Ekram MB1,2,3,10, Cohen O1,11, Kwak M12,13, Qin Y3,6,14, Laszewski T6, Luoma A15, Marusyk A1,2,3,16, Wucherpfennig KW15, Wagle N1,2,11, Fan R12,13, Michor F7,8,9,11,17,18, McAllister SS3,6,11,19, Polyak K20,21,22,23,24,25,26.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
2
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
3
Department of Medicine, Harvard Medical School, Boston, MA, USA.
4
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA.
5
Research Square, Durham, NC, USA.
6
Hematology Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
7
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
8
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
9
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
10
WuXi NextCODE, Cambridge, MA, USA.
11
The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge, MA, USA.
12
Department of Biomedical Engineering, Yale School of Medicine, New Haven, CT, USA.
13
Yale Comprehensive Cancer Center, New Haven, CT, USA.
14
EdiGene, Cambridge, MA, USA.
15
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
16
Department of Cancer Imaging and Metabolism, Moffitt Cancer Center, Tampa, FL, USA.
17
Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA, USA.
18
Ludwig Center at Harvard, Boston, MA, USA.
19
Harvard Stem Cell Institute, Cambridge, MA, USA.
20
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. kornelia_polyak@dfci.harvard.edu.
21
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. kornelia_polyak@dfci.harvard.edu.
22
Department of Medicine, Harvard Medical School, Boston, MA, USA. kornelia_polyak@dfci.harvard.edu.
23
The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge, MA, USA. kornelia_polyak@dfci.harvard.edu.
24
Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA, USA. kornelia_polyak@dfci.harvard.edu.
25
Ludwig Center at Harvard, Boston, MA, USA. kornelia_polyak@dfci.harvard.edu.
26
Harvard Stem Cell Institute, Cambridge, MA, USA. kornelia_polyak@dfci.harvard.edu.

Abstract

Most human tumours are heterogeneous, composed of cellular clones with different properties present at variable frequencies. Highly heterogeneous tumours have poor clinical outcomes, yet the underlying mechanism remains poorly understood. Here, we show that minor subclones of breast cancer cells expressing IL11 and FIGF (VEGFD) cooperate to promote metastatic progression and generate polyclonal metastases composed of driver and neutral subclones. Expression profiling of the epithelial and stromal compartments of monoclonal and polyclonal primary and metastatic lesions revealed that this cooperation is indirect, mediated through the local and systemic microenvironments. We identified neutrophils as a leukocyte population stimulated by the IL11-expressing minor subclone and showed that the depletion of neutrophils prevents metastatic outgrowth. Single-cell RNA-seq of CD45+ cell populations from primary tumours, blood and lungs demonstrated that IL11 acts on bone-marrow-derived mesenchymal stromal cells, which induce pro-tumorigenic and pro-metastatic neutrophils. Our results indicate key roles for non-cell-autonomous drivers and minor subclones in metastasis.

PMID:
31263265
PMCID:
PMC6609451
[Available on 2020-01-01]
DOI:
10.1038/s41556-019-0346-x

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