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

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)3916-3926.e5
JournalCell Reports
Volume27
Issue number13
DOIs
Publication statusPublished - 2019 Jun 25

Bibliographical note

Funding Information:
We thank Dr. Gary Luker for providing human immortalized fibroblasts, Dr. Sofia Merajver for providing VARI-068 cells, and Dr. Max Wicha for providing GUM36 cells. We are grateful to members of the Kleer laboratory for helpful discussions during this project. This work was supported by NIH grants R01CA125577 and R01CA107469 (C.G.K.), F30CA19084 (T.A.), P30CA046592, (C.G.K.) by the use of the following Cancer Center Shared Resources: Flow Cytometry, Cell & Tissue Imaging, and Tissue & Molecular Pathology, University of Michigan Office of Research (UMOR) grant 26998 (Y.-C.C.), and the Forbes Institute for Cancer Discovery (Y.-C.C.). C.G.K. and M.E.G. conceptualized and designed cell biology, in vivo experiments, human tissue analyses, analyzed data, and wrote the manuscript. Y.-C.C. and E.Y. conceptualized and developed the microfluidic engulfment platform and wrote the manuscript. Y.-C.C. performed on-chip experiments, transcriptome sequencing, and analyzed the data. Y.-H.C. assisted with the design of the microfluidic chip. W.L. and Y.C. helped with fabrication of the microfluidic devices. X.Z. and A.B.H. performed microfluidic engulfment assays. N.M. and T.A. assisted with performance and quantification of in vivo experiments and tissue sample analyses. B.B. performed biology assays and assisted with in vivo studies. M.T. interrogated breast cancer publicly available datasets. All authors helped to design the study and read the manuscript. E.Y. Y.-H.C. and Y.-C.C. filed a patent application on the microfluidic technology (application no. 62/449,867 and PCT/US2018/014353). The other authors declare no competing interests.

Funding Information:
We thank Dr. Gary Luker for providing human immortalized fibroblasts, Dr. Sofia Merajver for providing VARI-068 cells, and Dr. Max Wicha for providing GUM36 cells. We are grateful to members of the Kleer laboratory for helpful discussions during this project. This work was supported by NIH grants R01CA125577 and R01CA107469 (C.G.K.), F30CA19084 (T.A.), P30CA046592 , (C.G.K.) by the use of the following Cancer Center Shared Resources: Flow Cytometry, Cell & Tissue Imaging, and Tissue & Molecular Pathology, University of Michigan Office of Research (UMOR) grant 26998 (Y.-C.C.), and the Forbes Institute for Cancer Discovery (Y.-C.C.).

Publisher Copyright:
© 2019 The Author(s)

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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