RT Journal Article
SR Electronic
T1 Stromal fibroblasts induce metastatic tumor cell clusters via epithelial–mesenchymal plasticity
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900425
DO 10.26508/lsa.201900425
VO 2
IS 4
A1 Matsumura, Yuko
A1 Ito, Yasuhiko
A1 Mezawa, Yoshihiro
A1 Sulidan, Kaidiliayi
A1 Daigo, Yataro
A1 Hiraga, Toru
A1 Mogushi, Kaoru
A1 Wali, Nadila
A1 Suzuki, Hiromu
A1 Itoh, Takumi
A1 Miyagi, Yohei
A1 Yokose, Tomoyuki
A1 Shimizu, Satoru
A1 Takano, Atsushi
A1 Terao, Yasuhisa
A1 Saeki, Harumi
A1 Ozawa, Masayuki
A1 Abe, Masaaki
A1 Takeda, Satoru
A1 Okumura, Ko
A1 Habu, Sonoko
A1 Hino, Okio
A1 Takeda, Kazuyoshi
A1 Hamada, Michiaki
A1 Orimo, Akira
YR 2019
UL https://www.life-science-alliance.org/content/2/4/e201900425.abstract
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.