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

doi:10.1016/j.celrep.2019.05.084

Mesenchymal Stem/Stromal Cell Engulfment Reveals Metastatic Advantage in Breast Cancer

Cell Rep. 2019 Jun 25;27(13):3916-3926.e5. doi: 10.1016/j.celrep.2019.05.084.

Authors

Affiliations

¹ 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.
² Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
³ Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI 48109, USA.
⁴ 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.
⁵ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ 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.
⁷ Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: kleer@umich.edu.

Abstract

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.

Keywords: EZH2; MSC; breast cancer; cell engulfment; cell fusion; mesenchymal stem cell; metastasis; microenvironment; microfluidics; single cell retrieval.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Cell Line, Tumor
Female
Gene Expression Regulation, Neoplastic*
Humans
Mesenchymal Stem Cells / metabolism*
Mesenchymal Stem Cells / pathology
Mice
Mice, SCID
Neoplasm Metastasis
Neoplasm Proteins / metabolism*
Tumor Microenvironment*

Substances

Neoplasm Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding