Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts

Yosuke Mitsui, Nahoko Tomonobu, Masami Watanabe, Rie Kinoshita, I. Wayan Sumardika, Chen Youyi, Hitoshi Murata, Ken-ichi Yamamoto, Takuya Sadahira, Acosta Gonzalez Herik Rodrigo, Hitoshi Takamatsu, Kota Araki, Akira Yamauchi, Masahiro Yamamura, Hideyo Fujiwara, Yusuke Inoue, Junichiro Futami, Ken Saito, Hidekazu Iioka, Eisaku Kondo & 5 others Masahiro Nishibori, Shinichi Toyooka, Yasuhiko Yamamoto, Yasutomo Nasu, Masakiyo Sakaguchi

Research output: Contribution to journalArticle

Abstract

S100A11, a member of the S100 family of proteins, is actively secreted from pancreatic ductal adenocarcinoma (PDAC) cells. However, the role of the extracellular S100A11 in PDAC progression remains unclear. In the present study, we investigated the extracellular role of S100A11 in crosstalking between PDAC cells and surrounding fibroblasts in PDAC progression. An abundant S100A11 secreted from pancreatic cancer cells stimulated neighboring fibroblasts through receptor for advanced glycation end products (RAGE) upon S100A11 binding and was followed by not only an enhanced cancer cell motility in vitro but also an increased number of the PDAC-derived circulating tumor cells (CTCs) in vivo. Mechanistic investigation of RAGE downstream in fibroblasts revealed a novel contribution of a mitogen-activated protein kinase kinase kinase (MAPKKK), tumor progression locus 2 (TPL2), which is required for positive regulation of PDAC cell motility through induction of cyclooxygenase 2 (COX2) and its catalyzed production of prostaglandin E2 (PGE2), a strong chemoattractive fatty acid. The extracellularly released PGE2 from fibroblasts was required for the rise in cellular migration as well as infiltration of their adjacent PDAC cells in a coculture setting. Taken together, our data reveal a novel role of the secretory S100A11 in PDAC disseminative progression through activation of surrounding fibroblasts triggered by the S100A11-RAGE-TPL2-COX2 pathway. The findings of this study will contribute to the establishment of a novel therapeutic antidote to PDACs that are difficult to treat by regulating cancer-associated fibroblasts (CAFs) through targeting the identified pathway.

Original languageEnglish
Pages (from-to)945-956
Number of pages12
JournalOncology research
Volume27
Issue number8
DOIs
Publication statusPublished - Aug 8 2019

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Pancreatic Neoplasms
Adenocarcinoma
Up-Regulation
Fibroblasts
Cyclooxygenase 2
Dinoprostone
Cell Movement
MAP Kinase Kinase Kinases
Circulating Neoplastic Cells
Neoplasms
Antidotes
S100 Proteins
Coculture Techniques
Fatty Acids
Advanced Glycosylation End Product-Specific Receptor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts. / Mitsui, Yosuke; Tomonobu, Nahoko; Watanabe, Masami; Kinoshita, Rie; Sumardika, I. Wayan; Youyi, Chen; Murata, Hitoshi; Yamamoto, Ken-ichi; Sadahira, Takuya; Rodrigo, Acosta Gonzalez Herik; Takamatsu, Hitoshi; Araki, Kota; Yamauchi, Akira; Yamamura, Masahiro; Fujiwara, Hideyo; Inoue, Yusuke; Futami, Junichiro; Saito, Ken; Iioka, Hidekazu; Kondo, Eisaku; Nishibori, Masahiro; Toyooka, Shinichi; Yamamoto, Yasuhiko; Nasu, Yasutomo; Sakaguchi, Masakiyo.

In: Oncology research, Vol. 27, No. 8, 08.08.2019, p. 945-956.

Research output: Contribution to journalArticle

Mitsui, Y, Tomonobu, N, Watanabe, M, Kinoshita, R, Sumardika, IW, Youyi, C, Murata, H, Yamamoto, K, Sadahira, T, Rodrigo, AGH, Takamatsu, H, Araki, K, Yamauchi, A, Yamamura, M, Fujiwara, H, Inoue, Y, Futami, J, Saito, K, Iioka, H, Kondo, E, Nishibori, M, Toyooka, S, Yamamoto, Y, Nasu, Y & Sakaguchi, M 2019, 'Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts', Oncology research, vol. 27, no. 8, pp. 945-956. https://doi.org/10.3727/096504019X15555408784978
Mitsui, Yosuke ; Tomonobu, Nahoko ; Watanabe, Masami ; Kinoshita, Rie ; Sumardika, I. Wayan ; Youyi, Chen ; Murata, Hitoshi ; Yamamoto, Ken-ichi ; Sadahira, Takuya ; Rodrigo, Acosta Gonzalez Herik ; Takamatsu, Hitoshi ; Araki, Kota ; Yamauchi, Akira ; Yamamura, Masahiro ; Fujiwara, Hideyo ; Inoue, Yusuke ; Futami, Junichiro ; Saito, Ken ; Iioka, Hidekazu ; Kondo, Eisaku ; Nishibori, Masahiro ; Toyooka, Shinichi ; Yamamoto, Yasuhiko ; Nasu, Yasutomo ; Sakaguchi, Masakiyo. / Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts. In: Oncology research. 2019 ; Vol. 27, No. 8. pp. 945-956.
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AU - Mitsui, Yosuke

AU - Tomonobu, Nahoko

AU - Watanabe, Masami

AU - Kinoshita, Rie

AU - Sumardika, I. Wayan

AU - Youyi, Chen

AU - Murata, Hitoshi

AU - Yamamoto, Ken-ichi

AU - Sadahira, Takuya

AU - Rodrigo, Acosta Gonzalez Herik

AU - Takamatsu, Hitoshi

AU - Araki, Kota

AU - Yamauchi, Akira

AU - Yamamura, Masahiro

AU - Fujiwara, Hideyo

AU - Inoue, Yusuke

AU - Futami, Junichiro

AU - Saito, Ken

AU - Iioka, Hidekazu

AU - Kondo, Eisaku

AU - Nishibori, Masahiro

AU - Toyooka, Shinichi

AU - Yamamoto, Yasuhiko

AU - Nasu, Yasutomo

AU - Sakaguchi, Masakiyo

PY - 2019/8/8

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