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Summary: Twenty percent of breast cancer (BC) patients develop distant metastasis for which there is no cure. Mesenchymal stem/stromal cells (MSCs) in the tumor microenvironment were shown to stimulate metastasis, but the mechanisms are unclear. Here, we identified and quantified cancer cells engulfing stromal cells in clinical samples of BC metastasis by dual immunostaining for EZH2 and ALDH1 expression. Using flow cytometry and a microfluidic single-cell paring and retrieval platform, we show that MSC engulfment capacity is associated with BC cell metastatic potential and generates cells with mesenchymal-like, invasion, and stem cell traits. Whole-transcriptome analyses of selectively retrieved engulfing BC cells identify a gene signature of MSC engulfment consisting of WNT5A, MSR1, ELMO1, IL1RL2, ZPLD1, and SIRPB1. These results delineate a mechanism by which MSCs in the tumor microenvironment promote metastasis and provide a microfluidic platform with the potential to predict BC metastasis in clinical samples. : How MSCs in the tumor microenvironment promote breast cancer progression is unclear. Chen et al. find that aggressive breast cancer cells are able to engulf MSCs. Through the development of a microfluidic cell pairing platform, they discover that this process induces transcriptome changes in breast cancer cells and enhances distant metastasis. Keywords: breast cancer, metastasis, mesenchymal stem cell, MSC, cell fusion, cell engulfment, EZH2, microfluidics, microenvironment, single cell retrieval |
