TY - JOUR
T1 - Stromal fibroblasts induce metastatic tumor cell clusters via epithelial–mesenchymal plasticity
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
N1 - Funding Information:
We thank S Hatakeyama for the active Src cDNA construct, T Shibue for the tdTomato cDNA construct, Drs. RA Weinberg and M Kasai for reviewing the manuscript and giving critical comments and UM Polanska, N Kadowaki, K Miyahara, K Shimizu, T Takagaki, C Kataoka, T Kobayashi, K Kajino, Y Ono, and members of the laboratories of A Orimo, K Okumura, and O Hino for technical and general assistance. We also thank the Screening Committee for Anticancer Drugs supported by a Grant-in-Aid for Scientific Research on Innovative Areas, Scientific Support Programs for Cancer Research, from The Ministry of Education, Culture, Sports, Science and Technology, Japan, for chemical library support. This work was supported in part by a Grant-in-Aid for Scientific Research on Innovative Areas from The Japan Society for the Promotion of Science (JSPS KAKENHI grant number JP: 16H06277). Funding for this work was also provided by the Juntendo University Young Investigator Award (Y Matsumura), the Juntendo University Joint Project Award (Y Matsumura), and Cancer Research UK Grant C147/A6058 (to A Orimo), Grants in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (24300332, 25640069, and 15K14385 to A Orimo) and a Grant-in-Aid (S1311011) from the Foundation of Strategic Research Projects in Private Universities from the MEXT, Japan (A Orimo), and the Juntendo University School of Medicine, Research Institute for Diseases of Old Age (A Orimo).
Funding Information:
The chemical library including 358 chemical compounds was kindly provided by the Screening Committee of Anticancer Drugs supported by a Grant-in-Aid for Scientific Research on Innovative Areas, Scientific Support Programs for Cancer Research, from The Ministry of Education, Culture, Sports, Science and Technology, Japan. We seeded 1 × 105 DCISCAF2cy/well on 24-well culture plates and then treated them with each compound for 24 h before isolation of RNA and real-time PCR for CAM6 expression (Fig S5A).
Publisher Copyright:
© 2019 Matsumura et al.
PY - 2019
Y1 - 2019
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.
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.
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U2 - 10.26508/lsa.201900425
DO - 10.26508/lsa.201900425
M3 - Article
C2 - 31331982
AN - SCOPUS:85071198007
SN - 2575-1077
VL - 2
JO - Life Science Alliance
JF - Life Science Alliance
IS - 4
M1 - e201900425
ER -