Open Access

ARTICLE

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^§§, Masahiro Nishibori^¶¶, Shinichi Toyooka^§, Yasuhiko Yamamoto^##, Yasutomo Nasu^†, Masakiyo Sakaguchi^*

* Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
† Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
‡ Faculty of Medicine, Udayana University, Denpasar, Bali, Indonesia
§ Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
¶ Department of Biochemistry, Kawasaki Medical School, Kurashiki, Okayama, Japan
# Department of Clinical Oncology, Kawasaki Medical School, Kurashiki, Okayama, Japan
** Department of Pathology, Kawasaki Medical School, Kurashiki, Okayama, Japan
†† Faculty of Science and Technology, Division of Molecular Science, Gunma University, Kiryu, Gunma, Japan
‡‡ Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan
§§ Division of Molecular and Cellular Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
¶¶ Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
## Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan

Oncology Research 2019, 27(8), 945-956. https://doi.org/10.3727/096504019X15555408784978

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.

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