Stromal fibroblasts induce metastatic tumor cell clusters via epithelial–mesenchymal plasticity

Yuko Matsumura, Yasuhiko Ito, Yoshihiro Mezawa, Kaidiliayi Sulidan, Yataro Daigo, Toru Hiraga, Kaoru Mogushi, Nadila Wali, Hiromu Suzuki, Takumi Itoh, Yohei Miyagi, Tomoyuki Yokose, Satoru Shimizu, Atsushi Takano, Yasuhisa Terao, Harumi Saeki, Masayuki Ozawa, Masaaki Abe, Satoru Takeda, Ko OkumuraSonoko Habu, Okio Hino, Kazuyoshi Takeda, Michiaki Hamada, Akira Orimo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)


Emerging evidence supports the hypothesis that multicellular tumor clusters invade and seed metastasis. However, whether tumor-associated stroma induces epithelial–mesenchymal plasticity in tumor cell clusters, to promote invasion and metastasis, remains unknown. We demonstrate herein that carcinoma-associated fibroblasts (CAFs) frequently present in tumor stroma drive the formation of tumor cell clusters composed of two distinct cancer cell populations, one in a highly epithelial (E-cadherinhiZEB1lo/neg: Ehi) state and another in a hybrid epithelial/mesenchymal (E-cadherinloZEB1hi: E/M) state. The Ehi cells highly express oncogenic cell–cell adhesion molecules, such as carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and CEACAM6 that associate with E-cadherin, resulting in increased tumor cell cluster formation and metastatic seeding. The E/M cells also retain associations with Ehi cells, which follow the E/M cells leading to collective invasion. CAF-produced stromal cell-derived factor 1 and transforming growth factor-β confer the Ehi and E/M states as well as invasive and metastatic traits via Src activation in apposed human breast tumor cells. Taken together, these findings indicate that invasive and metastatic tumor cell clusters are induced by CAFs via epithelial–mesenchymal plasticity.

Original languageEnglish
Article numbere201900425
JournalLife Science Alliance
Issue number4
Publication statusPublished - 2019

ASJC Scopus subject areas

  • Ecology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Plant Science
  • Health, Toxicology and Mutagenesis


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