PT  - JOURNAL ARTICLE
AU  - Matsumura, Yuko
AU  - Ito, Yasuhiko
AU  - Mezawa, Yoshihiro
AU  - Sulidan, Kaidiliayi
AU  - Daigo, Yataro
AU  - Hiraga, Toru
AU  - Mogushi, Kaoru
AU  - Wali, Nadila
AU  - Suzuki, Hiromu
AU  - Itoh, Takumi
AU  - Miyagi, Yohei
AU  - Yokose, Tomoyuki
AU  - Shimizu, Satoru
AU  - Takano, Atsushi
AU  - Terao, Yasuhisa
AU  - Saeki, Harumi
AU  - Ozawa, Masayuki
AU  - Abe, Masaaki
AU  - Takeda, Satoru
AU  - Okumura, Ko
AU  - Habu, Sonoko
AU  - Hino, Okio
AU  - Takeda, Kazuyoshi
AU  - Hamada, Michiaki
AU  - Orimo, Akira
TI  - Stromal fibroblasts induce metastatic tumor cell clusters via epithelial–mesenchymal plasticity
AID  - 10.26508/lsa.201900425
DP  - 2019 Aug 01
TA  - Life Science Alliance
PG  - e201900425
VI  - 2
IP  - 4
4099  - http://www.life-science-alliance.org/content/2/4/e201900425.short
4100  - http://www.life-science-alliance.org/content/2/4/e201900425.full
SO  - Life Sci. Alliance2019 Aug 01; 2
AB  - 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.