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

Yuko Matsumura, Yasuhiko Ito, Yoshihiro Mezawa, Kaidiliayi Sulidan, Yataro Daigo, View ORCID ProfileToru Hiraga, Kaoru Mogushi, Nadila Wali, Hiromu Suzuki, View ORCID ProfileTakumi Itoh, Yohei Miyagi, View ORCID ProfileTomoyuki Yokose, Satoru Shimizu, Atsushi Takano, Yasuhisa Terao, Harumi Saeki, Masayuki Ozawa, Masaaki Abe, Satoru Takeda, Ko Okumura, Sonoko Habu, Okio Hino, View ORCID ProfileKazuyoshi Takeda, View ORCID ProfileMichiaki Hamada, View ORCID ProfileAkira Orimo  Correspondence email
Yuko Matsumura
1Department of Molecular Pathogenesis, Graduate School of Medicine, Juntendo University, Tokyo, Japan
2Department of Obstetrics and Gynecology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
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Yasuhiko Ito
1Department of Molecular Pathogenesis, Graduate School of Medicine, Juntendo University, Tokyo, Japan
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Yoshihiro Mezawa
1Department of Molecular Pathogenesis, Graduate School of Medicine, Juntendo University, Tokyo, Japan
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Kaidiliayi Sulidan
1Department of Molecular Pathogenesis, Graduate School of Medicine, Juntendo University, Tokyo, Japan
2Department of Obstetrics and Gynecology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
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Yataro Daigo
12Center for Antibody and Vaccine Therapy, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
13Department of Medical Oncology and Cancer Center, Shiga University of Medical Science, Otsu, Japan
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Toru Hiraga
7Department of Histology and Cell Biology, Matsumoto Dental University, Nagano, Japan
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  • ORCID record for Toru Hiraga
Kaoru Mogushi
8Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan
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Nadila Wali
1Department of Molecular Pathogenesis, Graduate School of Medicine, Juntendo University, Tokyo, Japan
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Hiromu Suzuki
15Department of Molecular Biology, School of Medicine, Sapporo Medical University, Hokkaido, Japan
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Takumi Itoh
1Department of Molecular Pathogenesis, Graduate School of Medicine, Juntendo University, Tokyo, Japan
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  • ORCID record for Takumi Itoh
Yohei Miyagi
9Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan
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Tomoyuki Yokose
10Department of Pathology, Kanagawa Cancer Center, Yokohama, Japan
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  • ORCID record for Tomoyuki Yokose
Satoru Shimizu
11Department of Breast and Endocrine Surgery, Kanagawa Cancer Center, Yokohama, Japan
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Atsushi Takano
12Center for Antibody and Vaccine Therapy, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
13Department of Medical Oncology and Cancer Center, Shiga University of Medical Science, Otsu, Japan
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Yasuhisa Terao
2Department of Obstetrics and Gynecology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
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Harumi Saeki
1Department of Molecular Pathogenesis, Graduate School of Medicine, Juntendo University, Tokyo, Japan
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Masayuki Ozawa
14Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
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Masaaki Abe
1Department of Molecular Pathogenesis, Graduate School of Medicine, Juntendo University, Tokyo, Japan
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Satoru Takeda
2Department of Obstetrics and Gynecology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
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Ko Okumura
4Atopy Research Center, Biomedical Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan
6Department of Biofunctional Microbiota, Graduate School of Medicine, Juntendo University, Tokyo, Japan
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Sonoko Habu
4Atopy Research Center, Biomedical Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan
6Department of Biofunctional Microbiota, Graduate School of Medicine, Juntendo University, Tokyo, Japan
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Okio Hino
1Department of Molecular Pathogenesis, Graduate School of Medicine, Juntendo University, Tokyo, Japan
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Kazuyoshi Takeda
5Division of Cell Biology, Biomedical Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan
6Department of Biofunctional Microbiota, Graduate School of Medicine, Juntendo University, Tokyo, Japan
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  • ORCID record for Kazuyoshi Takeda
Michiaki Hamada
3Department of Electrical Engineering and Bioscience, Faculty of Science and Engineering, Waseda University, Tokyo, Japan
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  • ORCID record for Michiaki Hamada
Akira Orimo
1Department of Molecular Pathogenesis, Graduate School of Medicine, Juntendo University, Tokyo, Japan
16Cancer Research (CR)-UK Stromal-Tumor Interaction Group, Paterson Institute for Cancer Research, The University of Manchester, Manchester, UK
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  • ORCID record for Akira Orimo
  • For correspondence: aorimo@juntendo.ac.jp
Published 22 July 2019. DOI: 10.26508/lsa.201900425
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Abstract

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.

  • Received May 11, 2019.
  • Revision received July 10, 2019.
  • Accepted July 10, 2019.
  • © 2019 Matsumura et al.
Creative Commons logoCreative Commons logohttps://creativecommons.org/licenses/by/4.0/

This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

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CAFs and partial EMT in tumor clusters.
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 Okumura, Sonoko Habu, Okio Hino, Kazuyoshi Takeda, Michiaki Hamada, Akira Orimo
Life Science Alliance Jul 2019, 2 (4) e201900425; DOI: 10.26508/lsa.201900425

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CAFs and partial EMT in tumor clusters.
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 Okumura, Sonoko Habu, Okio Hino, Kazuyoshi Takeda, Michiaki Hamada, Akira Orimo
Life Science Alliance Jul 2019, 2 (4) e201900425; DOI: 10.26508/lsa.201900425
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Volume 2, No. 4
August 2019
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