Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Nat Cell Biol. 2019 Jul;21(7):879-888. doi: 10.1038/s41556-019-0346-x. Epub 2019 Jul 1.
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.
大多数人类肿瘤是异质性的，由不同特性的细胞克隆以不同的频率存在。高度异质性的肿瘤具有较差的临床结局，但潜在的机制仍知之甚少。在这里，我们表明表达 IL11 和 FIGF（VEGFD）的乳腺癌细胞的次要亚克隆合作促进转移进展，并产生由驱动亚克隆和中性亚克隆组成的多克隆转移。对单克隆和多克隆原发性和转移性病变的上皮和基质区室进行表达谱分析表明，这种合作是间接的，通过局部和全身微环境介导的。我们确定中性粒细胞是受表达 IL11 的次要亚克隆刺激的白细胞群体，并表明中性粒细胞的耗竭可防止转移生长。来自原发性肿瘤、血液和肺部的 CD45 细胞群体的单细胞 RNA-seq 表明，IL11 作用于骨髓来源的间充质基质细胞，后者诱导促肿瘤发生和促转移的中性粒细胞。我们的结果表明，非细胞自主驱动因素和次要亚克隆在转移中起关键作用。
