Journal
NATURE CELL BIOLOGY
Volume 21, Issue 7, Pages 879-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41556-019-0346-x
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Funding
- Dana-Farber Cancer Institute Physical Sciences-Oncology Center [U54CA143798]
- Center for Cancer Evolution
- CDRMP Breast Cancer Research Program [W81XWH-09-1-0561, W81XWH-14-1-0191]
- Swiss National Science Foundation [P2EZP2 175139]
- NIH [K99/R00 CA201606-01A1, R35CA197623]
- Ludwig Center at Harvard
- Novartis Oncology
- Breast Cancer Research Foundation
- Swiss National Science Foundation (SNF) [P2EZP2_175139] Funding Source: Swiss National Science Foundation (SNF)
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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.
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