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.
Bibliographical noteFunding Information:
We thank the members of the Polyak and Michor laboratories for their critical reading of this manuscript and useful discussions. We thank L. Cameron from the DFCI Confocal Microscopy and Z. Herbert from the DFCI Molecular Biology Core Facility for their dedication and technical expertise. We also thank the staff of the DFCI Animal Facility for their help with the imaging studies. This work was supported by the Dana–Farber Cancer Institute Physical Sciences–Oncology Center (grant no. U54CA143798 to F.M. and K.P.) and Center for Cancer Evolution (F.M. and K.P.), CDRMP Breast Cancer Research Program (grant nos W81XWH-09-1-0561 (A.M.) and W81XWH-14-1-0191 (S.S.M)), Swiss National Science Foundation project no. P2EZP2 175139 (S.C.), NIH (grant nos K99/R00 CA201606-01A1 (M.J.) and R35CA197623 (K.P.)), the Ludwig Center at Harvard (F.M. and K.P.), Novartis Oncology (K.P.), and the Breast Cancer Research Foundation (K.P.).
All Science Journal Classification (ASJC) codes
- Cell Biology