Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments

Most human tumors are heterogeneous, composed of cellular clones with different properties present at variable frequencies. Highly heterogeneous tumors 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 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 depletion of neutrophils prevents metastatic outgrowth. Single-cell RNA-seq of CD45(+) cell populations from primary tumors, 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.