TY - JOUR T1 - Stromal fibroblasts induce metastatic tumor cell clusters via epithelial–mesenchymal plasticity JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201900425 VL - 2 IS - 4 SP - e201900425 AU - Yuko Matsumura AU - Yasuhiko Ito AU - Yoshihiro Mezawa AU - Kaidiliayi Sulidan AU - Yataro Daigo AU - Toru Hiraga AU - Kaoru Mogushi AU - Nadila Wali AU - Hiromu Suzuki AU - Takumi Itoh AU - Yohei Miyagi AU - Tomoyuki Yokose AU - Satoru Shimizu AU - Atsushi Takano AU - Yasuhisa Terao AU - Harumi Saeki AU - Masayuki Ozawa AU - Masaaki Abe AU - Satoru Takeda AU - Ko Okumura AU - Sonoko Habu AU - Okio Hino AU - Kazuyoshi Takeda AU - Michiaki Hamada AU - Akira Orimo Y1 - 2019/08/01 UR - https://www.life-science-alliance.org/content/2/4/e201900425.abstract N2 - 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. ER -