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Anti-tumor effect of trametinib in bladder cancer organoid and the underlying mechanism
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  • Mohamed Elbadawy,
  • Yomogi Sato,
  • Takashi Mori,
  • Yuta Goto,
  • Kimika Hayashi,
  • Megumi Yamanaka,
  • Daigo Azakami,
  • Tsuyoshi Uchide,
  • Ryuji Fukushima,
  • Toshinori Yoshida,
  • Makoto Shibutani,
  • Mio Kobayashi,
  • Yuta Shinohara,
  • Amira Abugomaa,
  • Masahiro Kaneda,
  • Hideyuki Yamawaki,
  • Tatsuya Usui,
  • Kazuaki Sasaki
Mohamed Elbadawy
Tokyo University of Agriculture and Technology
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Yomogi Sato
Tokyo University of Agriculture and Technology
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Takashi Mori
Gifu University
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Yuta Goto
Tokyo University of Agriculture and Technology
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Kimika Hayashi
Tokyo University of Agriculture and Technology
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Megumi Yamanaka
Tokyo University of Agriculture and Technology
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Daigo Azakami
Tokyo University of Agriculture and Technology
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Tsuyoshi Uchide
Tokyo University of Agriculture and Technology
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Ryuji Fukushima
Tokyo University of Agriculture and Technology
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Toshinori Yoshida
Tokyo University of Agriculture and Technology
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Makoto Shibutani
Tokyo University of Agriculture and Technology
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Mio Kobayashi
Tokyo University of Agriculture and Technology
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Yuta Shinohara
Tokyo University of Agriculture and Technology
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Amira Abugomaa
Tokyo University of Agriculture and Technology
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Masahiro Kaneda
Tokyo University of Agriculture and Technology
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Hideyuki Yamawaki
Kitasato University
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Tatsuya Usui
Tokyo University of Agriculture and Technology
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Kazuaki Sasaki
Tokyo University of Agriculture and Technology
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Abstract

Bladder cancer (BC), a main neoplasm of urinary tract, is usually inoperable and unresponsive to chemotherapy, indicating a necessity for more effective therapies. As a novel experimental model for muscle-invasive BC, we previously established a culture method of dog BC organoids. In the present study, the detailed in vitro and in vivo anti‐tumor effects of trametinib were investigated by using this model. In each BC organoid strain, epidermal growth factor receptor (EGFR)/ERK signaling was upregulated compared with normal bladder cells. Trametinib even at a low concentration inhibited the cell viability of BC organoids and the activation of ERK through decreasing expression of c-Myc, ELK1, SIK1, and PLA2G4A. Trametinib arrested cell cycle of BC with few apoptoses. Additionally, trametinib decreased expression of CD44, while YAP1 was unexpectedly upregulated. Dual treatment of BC organoids with trametinib and YAP inhibitor, verteporfin extremely inhibited the cell viability with apoptosis induction. Moreover, trametinib induced basal to luminal transformation of BC organoids by upregulating luminal markers (ERBB2 and GATA3) and downregulating basal ones (CK5 and DSG3). In vivo, trametinib decreased the tumor growth of BC organoids in mice and the xenograft-derived organoids from trametinib-administered mice showed enhanced sensitivity to carboplatin due to MSH2 upregulation. Our data suggested a new strategy of trametinib-YAP inhibitor or trametinib-carboplatin combination as a promising treatment of BC. Dog BC organoid model may hopefully become a promising research tool for human muscle-invasive BC in near future.