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2. Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy

Author

Koikawa, Kazuhiro, Kibe, Shin, Suizu, Futoshi, Sekino, Nobufumi, Kim, Nami, Manz, Theresa D., Pinch, Benika J., Akshinthala, Dipikaa, Verma, Ana, Gaglia, Giorgio, Nezu, Yutaka, Ke, Shizhong, Qiu, Chenxi, Ohuchida, Kenoki, Oda, Yoshinao, Lee, Tae Ho, Wegiel, Babara, Clohessy, John G., London, Nir, Santagata, Sandro, Wulf, Gerburg M., Hidalgo, Manuel, Muthuswamy, Senthil K., Nakamura, Masafumi, Gray, Nathanael S., Zhou, Xiao Zhen, and Lu, Kun Ping

Published
2021
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3. Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo

Author

Dubiella, Christian, Pinch, Benika J., Koikawa, Kazuhiro, Zaidman, Daniel, Poon, Evon, Manz, Theresa D., Nabet, Behnam, He, Shuning, Resnick, Efrat, Rogel, Adi, Langer, Ellen M., Daniel, Colin J., Seo, Hyuk-Soo, Chen, Ying, Adelmant, Guillaume, Sharifzadeh, Shabnam, Ficarro, Scott B., Jamin, Yann, Martins da Costa, Barbara, Zimmerman, Mark W., Lian, Xiaolan, Kibe, Shin, Kozono, Shingo, Doctor, Zainab M., Browne, Christopher M., Yang, Annan, Stoler-Barak, Liat, Shah, Richa B., Vangos, Nicholas E., Geffken, Ezekiel A., Oren, Roni, Koide, Eriko, Sidi, Samuel, Shulman, Ziv, Wang, Chu, Marto, Jarrod A., Dhe-Paganon, Sirano, Look, Thomas, Zhou, Xiao Zhen, Lu, Kun Ping, Sears, Rosalie C., Chesler, Louis, Gray, Nathanael S., and London, Nir

Published
2021
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4. Identification of a potent and selective covalent Pin1 inhibitor

Author

Pinch, Benika J., Doctor, Zainab M., Nabet, Behnam, Browne, Christopher M., Seo, Hyuk-Soo, Mohardt, Mikaela L., Kozono, Shingo, Lian, Xiaolan, Manz, Theresa D., Chun, Yujin, Kibe, Shin, Zaidman, Daniel, Daitchman, Dina, Yeoh, Zoe C., Vangos, Nicholas E., Geffken, Ezekiel A., Tan, Li, Ficarro, Scott B., London, Nir, Marto, Jarrod A., Buratowski, Stephen, Dhe-Paganon, Sirano, Zhou, Xiao Zhen, Lu, Kun Ping, and Gray, Nathanael S.

Published
2020
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7. Pancreatic stellate cells reorganize matrix components and lead pancreatic cancer invasion via the function of Endo180

Author

Koikawa, Kazuhiro, Ohuchida, Kenoki, Takesue, Shin, Ando, Yohei, Kibe, Shin, Nakayama, Hiromichi, Endo, Sho, Abe, Toshiya, Okumura, Takashi, Horioka, Kohei, Sada, Masafumi, Iwamoto, Chika, Moriyama, Taiki, Nakata, Kohei, Miyasaka, Yoshihiro, Ohuchida, Riichi, Manabe, Tatsuya, Ohtsuka, Takao, Nagai, Eishi, Mizumoto, Kazuhiro, Hashizume, Makoto, and Nakamura, Masafumi

Published
2018
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11. Identification of a potent and selective covalent Pin1 inhibitor

Author

Pinch, Benika J., Doctor, Zainab M., Nabet, Behnam, Browne, Christopher M., Seo, Hyuk-Soo, Mohardt, Mikaela L., Kozono, Shingo, Lian, Xiaolan, Manz, Theresa D., Chun, Yujin, Kibe, Shin, Zaidman, Daniel, Daitchman, Dina, Yeoh, Zoe C., Vangos, Nicholas E., Geffken, Ezekiel A., Tan, Li, Ficarro, Scott B., London, Nir, Marto, Jarrod A., Buratowski, Stephen, Dhe-Paganon, Sirano, Zhou, Xiao Zhen, Lu, Kun Ping, and Gray, Nathanael S.

Abstract

Peptidyl-prolyl cis/transisomerase NIMA-interacting 1 (Pin1) is commonly overexpressed in human cancers, including pancreatic ductal adenocarcinoma (PDAC). While Pin1 is dispensable for viability in mice, it is required for activated Ras to induce tumorigenesis, suggesting a role for Pin1 inhibitors in Ras-driven tumors, such as PDAC. We report the development of rationally designed peptide inhibitors that covalently target Cys113, a highly conserved cysteine located in the Pin1 active site. The inhibitors were iteratively optimized for potency, selectivity and cell permeability to give BJP-06-005-3, a versatile tool compound with which to probe Pin1 biology and interrogate its role in cancer. In parallel to inhibitor development, we employed genetic and chemical-genetic strategies to assess the consequences of Pin1 loss in human PDAC cell lines. We demonstrate that Pin1 cooperates with mutant KRAS to promote transformation in PDAC, and that Pin1 inhibition impairs cell viability over time in PDAC cell lines.

Published
2024
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14. Sulfopin, a selective covalent inhibitor of Pin1, blocks Myc-driven tumor initiation and growthin vivo

Author

Dubiella, Christian, primary, Pinch, Benika J., additional, Zaidman, Daniel, additional, Manz, Theresa D., additional, Poon, Evon, additional, He, Shuning, additional, Resnick, Efrat, additional, Langer, Ellen M., additional, Daniel, Colin J., additional, Seo, Hyuk-Soo, additional, Chen, Ying, additional, Ficarro, Scott B., additional, Jamin, Yann, additional, Lian, Xiaolan, additional, Kibe, Shin, additional, Kozono, Shingo, additional, Koikawa, Kazuhiro, additional, Doctor, Zainab M., additional, Nabet, Behnam, additional, Browne, Christopher M., additional, Yang, Annan, additional, Stoler-Barak, Liat, additional, Shah, Richa B., additional, Vangos, Nick E., additional, Geffken, Ezekiel A., additional, Oren, Roni, additional, Sidi, Samuel, additional, Shulman, Ziv, additional, Wang, Chu, additional, Marto, Jarrod A., additional, Dhe-Paganon, Sirano, additional, Look, Thomas, additional, Zhou, Xiao Zhen, additional, Lu, Kun Ping, additional, Sears, Rosalie C., additional, Chesler, Louis, additional, Gray, Nathanael S., additional, and London, Nir, additional

Published
2020
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15. Additional file 1: of Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis

Author

Zilong Yan, Kenoki Ohuchida, Fei, Shuang, Zheng, Biao, Weiyu Guan, Haimin Feng, Kibe, Shin, Ando, Yohei, Koikawa, Kazuhiro, Abe, Toshiya, Iwamoto, Chika, Shindo, Koji, Moriyama, Taiki, Nakata, Kohei, Miyasaka, Yoshihiro, Ohtsuka, Takao, Mizumoto, Kazuhiro, Hashizume, Makoto, and Nakamura, Masafumi

Subjects
endocrine system diseases
Abstract

Figure S1. Characteristics of highly metastatic PDAC cells. (A) Suspended cell viability of cancer cells as determined by CellTiter-Glo luminescent cell viability assay. **P

Published
2019
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16. Additional file 5: of Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancerâ stromal interaction and metastasis

Author

Zilong Yan, Kenoki Ohuchida, Fei, Shuang, Zheng, Biao, Weiyu Guan, Haimin Feng, Kibe, Shin, Ando, Yohei, Koikawa, Kazuhiro, Abe, Toshiya, Iwamoto, Chika, Shindo, Koji, Moriyama, Taiki, Nakata, Kohei, Miyasaka, Yoshihiro, Ohtsuka, Takao, Mizumoto, Kazuhiro, Hashizume, Makoto, and Nakamura, Masafumi

Abstract

Table S1. Primers used for quantitative RT-PCR. (DOCX 56 kb)

Published
2019
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17. Additional file 2: of Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancerâ stromal interaction and metastasis

Author

Zilong Yan, Kenoki Ohuchida, Fei, Shuang, Zheng, Biao, Weiyu Guan, Haimin Feng, Kibe, Shin, Ando, Yohei, Koikawa, Kazuhiro, Abe, Toshiya, Iwamoto, Chika, Shindo, Koji, Moriyama, Taiki, Nakata, Kohei, Miyasaka, Yoshihiro, Ohtsuka, Takao, Mizumoto, Kazuhiro, Hashizume, Makoto, and Nakamura, Masafumi

Subjects
endocrine system diseases
Abstract

Figure S2. Expression and prognosis of p-ERK1/2 in PDAC database. (A) ERK1 and (B) ERK2 expression was detected in both cancer and stromal cells in human pancreatic primary tumor. (C, D) Kaplanâ Meier survival analysis of overall survival and disease-free survival of patients with pancreatic cancer by ERK1 and ERK2 mRNA expression. (PDF 262364 kb)

Published
2019
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18. Additional file 3: of Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis

Author

Zilong Yan, Kenoki Ohuchida, Fei, Shuang, Zheng, Biao, Weiyu Guan, Haimin Feng, Kibe, Shin, Ando, Yohei, Koikawa, Kazuhiro, Abe, Toshiya, Iwamoto, Chika, Shindo, Koji, Moriyama, Taiki, Nakata, Kohei, Miyasaka, Yoshihiro, Ohtsuka, Takao, Mizumoto, Kazuhiro, Hashizume, Makoto, and Nakamura, Masafumi

Abstract

Figure S3. Dual-treatment with SCH772984 and CQ decreased cell viability and induced PSC2 senescence. (A) Microphotograph of PSC2 cells after treatment with indicated agents. Scale bars = 100 μm. (B) Viability of PSCs after treatment with indicated agents. (C) qRT-PCR showed mRNA expression of α-SMA, Collagen Type I, p15 and p16. *P

Published
2019
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19. Additional file 4: of Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis

Author

Zilong Yan, Kenoki Ohuchida, Fei, Shuang, Zheng, Biao, Weiyu Guan, Haimin Feng, Kibe, Shin, Ando, Yohei, Koikawa, Kazuhiro, Abe, Toshiya, Iwamoto, Chika, Shindo, Koji, Moriyama, Taiki, Nakata, Kohei, Miyasaka, Yoshihiro, Ohtsuka, Takao, Mizumoto, Kazuhiro, Hashizume, Makoto, and Nakamura, Masafumi

Abstract

Figure S4. Pancreatic tumor organoid recapitulates p-ERK1/2 expression of PDAC in vitro and in vivo. (A) Western blot of ERK1/2 and p-ERK1/2 shows increasing p-ERK1/2 level in KPC cancer organoid compared with cancer cells. (B) Scheme of xenograft experiment. Mice were randomly divided into two groups and 5 × 104 cancer cells or organoids were intrasplenic implanted with 5 × 104 PSCs. After 2 weeks, liver metastases were evaluated. (C) H&E staining and immunohistochemical staining show metastatic nodules (D), and expression of α-SMA (E) and p-ERK1/2 (F). (G, H) Combination of indicated dose of SCH772984 improved chemosensitivity of gemcitabine of AsPC-1 and SUIT-2 cells in the PSC-conditioned medium. Columns, mean fold changes of three experiments done in triplicate. (PDF 262364 kb)

Published
2019
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20. Necroptosis in pancreatic cancer promotes cancer cell migration and invasion by release of CXCL5

Author

Ando, Yohei, primary, Ohuchida, Kenoki, additional, Otsubo, Yoshiki, additional, Kibe, Shin, additional, Takesue, Shin, additional, Abe, Toshiya, additional, Iwamoto, Chika, additional, Shindo, Koji, additional, Moriyama, Taiki, additional, Nakata, Kohei, additional, Miyasaka, Yoshihiro, additional, Ohtsuka, Takao, additional, Oda, Yoshinao, additional, and Nakamura, Masafumi, additional

Published
2020
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21. Neutrophil extracellular traps promote liver micrometastasis in pancreatic ductal adenocarcinoma via the activation of cancer‑associated fibroblasts

Author

Takesue, Shin, primary, Ohuchida, Kenoki, additional, Shinkawa, Tomohiko, additional, Otsubo, Yoshiki, additional, Matsumoto, Sokichi, additional, Sagara, Akiko, additional, Yonenaga, Akiko, additional, Ando, Yohei, additional, Kibe, Shin, additional, Nakayama, Hiromichi, additional, Iwamoto, Chika, additional, Shindo, Koji, additional, Moriyama, Taiki, additional, Nakata, Kohei, additional, Miyasaka, Yoshihiro, additional, Ohtsuka, Takao, additional, Toma, Hiroki, additional, Tominaga, Yohei, additional, Mizumoto, Kazuhiro, additional, Hashizume, Makoto, additional, and Nakamura, Masafumi, additional

Published
2019
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22. S100P regulates the collective invasion of pancreatic cancer cells into the lymphatic endothelial monolayer

Author

Nakayama, Hiromichi, primary, Ohuchida, Kenoki, additional, Yonenaga, Akiko, additional, Sagara, Akiko, additional, Ando, Yohei, additional, Kibe, Shin, additional, Takesue, Shin, additional, Abe, Toshiya, additional, Endo, Sho, additional, Koikawa, Kazuhiro, additional, Okumura, Takashi, additional, Shido, Koji, additional, Miyoshi, Kei, additional, Nakata, Kohei, additional, Moriyama, Taiki, additional, Miyasaka, Yoshihiro, additional, Inoue, Shigetaka, additional, Ohtsuka, Takao, additional, Mizumoto, Kazuhiro, additional, and Nakamura, Masafumi, additional

Published
2019
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23. Adipose tissue-derived stromal cells are sources of cancer-associated fibroblasts and enhance tumor progression by dense collagen matrix

Author

Okumura, Takashi, primary, Ohuchida, Kenoki, additional, Kibe, Shin, additional, Iwamoto, Chika, additional, Ando, Yohei, additional, Takesue, Shin, additional, Nakayama, Hiromichi, additional, Abe, Toshiya, additional, Endo, Sho, additional, Koikawa, Kazuhiro, additional, Sada, Masafumi, additional, Horioka, Kohei, additional, Mochidome, Naoki, additional, Arita, Makoto, additional, Moriyama, Taiki, additional, Nakata, Kohei, additional, Miyasaka, Yoshihiro, additional, Ohtsuka, Takao, additional, Mizumoto, Kazuhiro, additional, Oda, Yoshinao, additional, Hashizume, Makoto, additional, and Nakamura, Masafumi, additional

Published
2018
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24. 104 - Pancreatic Stellate Cells Induce Basement Membrane Destruction and Lead Cancer Cell Invasion in Pancreatic Ductal Adenocarcinoma

Author

Koikawa, Kazuhiro, primary, Ohuchida, Kenoki, additional, Ando, Yohei, additional, Kibe, Shin, additional, Nakayama, Hiromichi, additional, Takesue, Shin, additional, Endo, Sho, additional, Abe, Toshiya, additional, Okumura, Takashi, additional, Iwamoto, Chika, additional, Shindo, Koji, additional, Moriyama, Taiki, additional, Nakata, Kohei, additional, Miyasaka, Yoshihiro, additional, Ohtsuka, Takao, additional, Mizumoto, Kazuhiro, additional, and Nakamura, Masafumi, additional

Published
2018
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25. 306 - BM-Derived Cells Recruited to the Pancreas Constitute the Tumor Microenvironment and Promote Invasion of Pancreatic Cancer

Author

Iwamoto, Chika, primary, Ohuchida, Kenoki, additional, Okumura, Takashi, additional, Koikawa, Kazuhiro, additional, Takesue, Shin, additional, Nakayama, Hiromichi, additional, Endo, Sho, additional, Kibe, Shin, additional, Ando, Yohei, additional, Miyawaki, Kohta, additional, Murata, Masaharu, additional, Akashi, Koichi, additional, Nakamura, Masafumi, additional, and Hashizume, Makoto, additional

Published
2018
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26. Tu1359 - The Role of Cancer-Associated Acinar Atrophy via Adm-Like Lesion in the Invasive Front of Pancreatic Cancer

Author

Kibe, Shin, primary, Ohuchida, Kenoki, additional, Ando, Yohei, additional, Takesue, Shin, additional, Nakayama, Hiromichi, additional, Abe, Toshiya, additional, Endo, Sho, additional, Koikawa, Kazuhiro, additional, Okumura, Takashi, additional, Shindo, Koji, additional, Moriyama, Taiki, additional, Nakata, Kohei, additional, Nagai, Shuntaro, additional, Miyasaka, Yoshihiro, additional, Ohtsuka, Takao, additional, Mizumoto, Kazuhiro, additional, and Nakamura, Masafumi, additional

Published
2018
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27. Sa1377 - Necroptosis Promotes Cancer Cell Migration and Invasion in Pancreatic Cancer

Author

Ando, Yohei, primary, Ohuchida, Kenoki, additional, Kibe, Shin, additional, Takesue, Shin, additional, Nakayama, Hiromichi, additional, Koikawa, Kazuhiro, additional, Shindo, Koji, additional, Moriyama, Taiki, additional, Nakata, Kohei, additional, Miyasaka, Yoshihiro, additional, Ohtsuka, Takao, additional, Mizumoto, Kazuhiro, additional, and Nakamura, Masafumi, additional

Published
2018
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30. AB025. S025. Basement membrane destruction by pancreatic stellate cells leads to local invasion in pancreatic ductal adenocarcinoma

Author

Koikawa, Kazuhiro, primary, Ohuchida, Kenoki, additional, Ando, Yohei, additional, Kibe, Shin, additional, Nakayama, Hiromichi, additional, Takesue, Shin, additional, Endo, Sho, additional, Abe, Toshiya, additional, Okumura, Takashi, additional, Iwamoto, Chika, additional, Shindo, Koji, additional, Moriyama, Taiki, additional, Nakata, Kohei, additional, Miyasaka, Yoshihiro, additional, Ohtsuka, Takao, additional, Nagai, Eishi, additional, Mizumoto, Kazuhiro, additional, Hashizume, Makoto, additional, and Nakamura, Masafumi, additional

Published
2018
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31. AB036. P007. BM-derived cells differentiated into multilineage hematopoietic cells regulate invasion and proliferation of pancreatic cancer

Author

Iwamoto, Chika, primary, Ohuchida, Kenoki, additional, Okumura, Takashi, additional, Koikawa, Kazuhiro, additional, Takesue, Shin, additional, Nakayama, Hiromichi, additional, Endo, Sho, additional, Kibe, Shin, additional, Ando, Yohei, additional, Shindo, Koji, additional, Nakata, Kohei, additional, Miyawaki, Kohta, additional, Murata, Masaharu, additional, Akashi, Koichi, additional, Nakamura, Masafumi, additional, and Hashizume, Makoto, additional

Published
2018
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32. Neutrophil extracellular traps promote liver micrometastasis in pancreatic ductal adenocarcinoma via the activation of cancer-associated fibroblasts.

Author

Takesue, Shin, Ohuchida, Kenoki, Shinkawa, Tomohiko, Otsubo, Yoshiki, Matsumoto, Sokichi, Sagara, Akiko, Yonenaga, Akiko, Ando, Yohei, Kibe, Shin, Nakayama, Hiromichi, Iwamoto, Chika, Shindo, Koji, Moriyama, Taiki, Nakata, Kohei, Miyasaka, Yoshihiro, Ohtsuka, Takao, Toma, Hiroki, Tominaga, Yohei, Mizumoto, Kazuhiro, and Hashizume, Makoto

Published
2020
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33. Adipose tissue‐derived stromal cells are sources of cancer‐associated fibroblasts and enhance tumor progression by dense collagen matrix.

Author

Okumura, Takashi, Ohuchida, Kenoki, Kibe, Shin, Iwamoto, Chika, Ando, Yohei, Takesue, Shin, Nakayama, Hiromichi, Abe, Toshiya, Endo, Sho, Koikawa, Kazuhiro, Sada, Masafumi, Horioka, Kohei, Mochidome, Naoki, Arita, Makoto, Moriyama, Taiki, Nakata, Kohei, Miyasaka, Yoshihiro, Ohtsuka, Takao, Mizumoto, Kazuhiro, and Oda, Yoshinao

Abstract

Although recent studies revealed that adipose tissue accelerates pancreatic tumor progression with excessive extracellular matrix, key players for desmoplasia in the adipose microenvironment remains unknown. Here, we investigated the roles of adipose tissue‐derived stromal cells (ASCs) in desmoplastic lesions and tumor progression by in vitro and in vivo experiments. In a three‐dimensional (3‐D) organotypic fat invasion model using visceral fat from CAG‐EGFP mice, GFP‐positive fibroblastic cells infiltrated toward cancer cells. When tumor cells were inoculated into transplanted visceral fat pads in vivo, tumor weights and stromal components were enhanced compared to subcutaneous and orthotopic tumor cells inoculated without fat pads. Expression of αSMA in established human ASCs was lower compared to cancer associated fibroblasts, and the 3‐D collagen matrices produced by ASCs cultured in cancer cell‐conditioned medium changed from loose to dense structures that affected the motility of cancer cells. Microarray analyses revealed upregulation of S100A4 in ASCs, while S100A4‐positive stromal cells were observed at extrapancreatic invasion sites of human pancreatic cancer. The present findings indicate that ASCs are recruited to extrapancreatic invasion sites and produce dense collagen matrices that lead to enhanced tumor progression. Both inhibition of ASCs recruitment and activation could lead to a novel antistromal therapy. What's new? One of the major pathological features of pancreatic ductal adenocarcinoma is excessive stromal involvement, and anti‐stromal therapies are considered promising against this deadly cancer. Here the authors show in a 3D organotypic fat invasion model or in mice specific infiltration of adipose tissue‐derived stromal cells towards cancer cells and dense collagen production leading to enhanced tumor progression in vivo. They speculate that adipose‐derived stromal cells may be new targets in therapy approaches against pancreatic cancer. [ABSTRACT FROM AUTHOR]

Published
2019
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35. Validity of the management strategy for intraductal papillary mucinous neoplasm advocated by the international consensus guidelines 2012: a retrospective review

Author

Watanabe, Yusuke, primary, Nishihara, Kazuyoshi, additional, Niina, Yusuke, additional, Abe, Yuji, additional, Amaike, Takao, additional, Kibe, Shin, additional, Mizuuchi, Yusuke, additional, Kakihara, Daisuke, additional, Ono, Minoru, additional, Tamiya, Sadafumi, additional, Toyoshima, Satoshi, additional, Nakano, Toru, additional, and Mitsuyama, Shoshu, additional

Published
2015
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36. A Case of Spontaneous Mesenteric Hematoma

Author

KIBE, Shin, primary, MAEYAMA, Ryo, additional, NAKATA, Kouhei, additional, MOTOSHITA, Junichi, additional, KONOMI, Hiroyuki, additional, OOKIDO, Masayuki, additional, and ICHIMIYA, Hitoshi, additional

Published
2015
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