Mesenchymal Stem/Stromal Cell Engulfment Reveals Metastatic Advantage in Breast Cancer
Yu-Chih Chen,
Maria E. Gonzalez,
Boris Burman,
Xintao Zhao,
Talha Anwar,
Mai Tran,
Natasha Medhora,
Ayse B. Hiziroglu,
Woncheol Lee,
Yu-Heng Cheng,
Yehyun Choi,
Euisik Yoon,
Celina G. Kleer
Affiliations
Yu-Chih Chen
Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI 48109, USA; Forbes Institute for Cancer Discovery, University of Michigan, Ann Arbor, MI 48109, USA
Maria E. Gonzalez
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
Boris Burman
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
Xintao Zhao
Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI 48109, USA
Talha Anwar
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Molecular Cellular and Pathology Training Program, University of Michigan, Ann Arbor, MI 48109, USA; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI 48109, USA
Mai Tran
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
Natasha Medhora
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
Ayse B. Hiziroglu
Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
Woncheol Lee
Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI 48109, USA
Yu-Heng Cheng
Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI 48109, USA
Yehyun Choi
Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI 48109, USA
Euisik Yoon
Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
Celina G. Kleer
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Corresponding author
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
