Faculty Profiles - ENOMOTO, Atsushi

Papers - ENOMOTO, Atsushi

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免疫チェックポイント阻害剤を用いた膵癌治療:基礎から臨床まで癌関連線維芽細胞をターゲットにした免疫チェックポイント阻害剤感受性改善薬の開発

飯田忠, 榎本篤, 川嶋啓揮

膵臓 Vol. 38 ( 3 ) page： A211 - A211 2023.7

Significance of expression of CD109 in osteosarcoma and its involvement in tumor progression<i> via</i> BMP signaling

Mori, N; Esaki, N; Shimoyama, Y; Shiraki, Y; Asai, N; Sakai, T; Nishida, Y; Takahashi, M; Enomoto, A; Mii, S

PATHOLOGY RESEARCH AND PRACTICE Vol. 245 page： 154443 2023.5

Neuroendocrine neoplasms of the breast: diagnostic confusion and future perspectives. International journal

Tomonori Kawasaki, Tomoaki Tashima, Atsushi Enomoto, Tetsuo Kondo, Hirokazu Nagai, Yasuhiro Nakamura, Jiro Ichikawa, Kiyomi Taniyama, Kyoichi Kaira

Virchows Archiv : an international journal of pathology Vol. 482 ( 5 ) page： 929 - 930 2023.5

Substrate stiffness induces nuclear localization of myosin regulatory light chain to suppress apoptosis. Reviewed International journal

Katsuya Onishi, Seiichiro Ishihara, Masayuki Takahashi, Akihiro Sakai, Atsushi Enomoto, Kentaro Suzuki, Hisashi Haga

FEBS letters Vol. 597 ( 5 ) page： 643 - 656 2023.3

Language：English Publishing type：Research paper (scientific journal)

Stiffness of the extracellular matrix regulates various biological responses, but the response mechanisms are poorly understood. Here, we found that the nuclear diphosphorylated myosin regulatory light chain (2P-MRLC) is a critical mechanomediator that suppresses apoptosis in response to substrate stiffness. Stiff substrates promoted the nuclear localization of 2P-MRLC. Zipper-interacting protein kinase [ZIPK; also known as death-associated protein kinase 3 (DAPK3)], a kinase for MRLC, was localized in the nucleus in response to stiff substrates and promoted the nuclear localization of 2P-MRLC. Moreover, actin fiber formation induced by substrate stiffness promoted the nuclear localization of 2P-MRLC via ZIPK. 2P-MRLC in response to substrate stiffness suppressed the expression of MAF bZIP transcription factor B (MafB) and repressed apoptosis. These findings reveal a newly identified role of MRLC in mechanotransduction.

DOI： 10.1002/1873-3468.14592

Web of Science

PubMed

The usefulness of meflin expression in cancer-associated fibroblasts as a predictive marker for immune checkpoint inhibitor in clear cell renal cell carcinoma.

Owaki, T; Miyai, Y; Naito, Y; Sano, T; Enomoto, A

JOURNAL OF CLINICAL ONCOLOGY Vol. 41 2023.2

Stiff substrates localize myosin regulatory light chain in nucleus to suppress apoptosis

Katsuya, O; Seiichiro, I; Masayuki, T; Enomoto, A; Haga, H

MOLECULAR BIOLOGY OF THE CELL Vol. 34 ( 2 ) page： 731 - 732 2023.2

TGF-β signaling promotes desmoid tumor formation in a mouse model

Li, Y; Fujishita, T; Mishiro, E; Taketo, MM; Enomoto, A; Nishida, Y; Aoki, M

CANCER SCIENCE Vol. 114 page： 1833 - 1833 2023.2

An Effective Therapy that Antibody-Drug Conjugates Targeting Meflin (+) Cells for Osteosarcoma

Sakoda, T; Esaki, N; Ando, R; Miyai, Y; Iida, T; Matsuyama, M; Shiraki, Y; Mii, S; Nishida, Y; Takahashi, M; Enomoto, A

CANCER SCIENCE Vol. 114 page： 760 - 760 2023.2

Cancer-associated Fibroblast-derived Itaconate in Tumor Microenvironment Promotes Tumor Growth in Cervical Cancer

Nakahara, R; Aki, S; Kato, M; Tsuchida, R; Shimamura, T; Enomoto, A; Osawa, T

CANCER SCIENCE Vol. 114 page： 1779 - 1779 2023.2

Cancer-associated Fibroblast-derived Itaconate in Tumor Microenvironment Promotes Tumor Growth in Cervical Cancer

Nakahara, R; Aki, S; Kato, M; Tsuchida, R; Shimamura, T; Enomoto, A; Osawa, T

CANCER SCIENCE Vol. 114 page： 1923 - 1923 2023.2

Identification of tumor suppressor fibroblasts and therapeutic applications

Iida, T; Mizutani, Y; Kawashima, H; Enomoto, A

CANCER SCIENCE Vol. 114 page： 1650 - 1650 2023.2

Meflin is a good predictive biomarker for ICI in urothelial carcinoma

Owaki, T; Miyai, Y; Iida, T; Esaki, N; Shiraki, Y; Mii, S; Enomoto, A

CANCER SCIENCE Vol. 114 page： 1399 - 1399 2023.2

New horizons for cancer research driven by histopathological approaches

Enomoto, A; Kanai, Y

CANCER SCIENCE Vol. 114 page： 919 - 919 2023.2

Peritoneal restoration by repurposing vitamin D inhibits ovarian cancer dissemination via blockade of TGF-β1/THBS1

Kitami, K; Yoshihara, M; Yamakita, Y; Sugiyama, M; Koya, Y; Miyamoto, E; Fujimoto, H; Iyoshi, S; Uno, K; Mogi, K; Kato, K; Nawa, A; Enomoto, A; Kajiyama, H

CANCER SCIENCE Vol. 114 page： 1047 - 1047 2023.2

Therapeutic Strategies to Overcome Fibrotic Barriers to Nanomedicine in the Pancreatic Tumor Microenvironment. Reviewed International journal

Hiroyoshi Y Tanaka, Takuya Nakazawa, Atsushi Enomoto, Atsushi Masamune, Mitsunobu R Kano

Cancers Vol. 15 ( 3 ) 2023.2

Language：English Publishing type：Research paper (scientific journal)

Pancreatic cancer is notorious for its dismal prognosis. The enhanced permeability and retention (EPR) effect theory posits that nanomedicines (therapeutics in the size range of approximately 10-200 nm) selectively accumulate in tumors. Nanomedicine has thus been suggested to be the "magic bullet"-both effective and safe-to treat pancreatic cancer. However, the densely fibrotic tumor microenvironment of pancreatic cancer impedes nanomedicine delivery. The EPR effect is thus insufficient to achieve a significant therapeutic effect. Intratumoral fibrosis is chiefly driven by aberrantly activated fibroblasts and the extracellular matrix (ECM) components secreted. Fibroblast and ECM abnormalities offer various potential targets for therapeutic intervention. In this review, we detail the diverse strategies being tested to overcome the fibrotic barriers to nanomedicine in pancreatic cancer. Strategies that target the fibrotic tissue/process are discussed first, which are followed by strategies to optimize nanomedicine design. We provide an overview of how a deeper understanding, increasingly at single-cell resolution, of fibroblast biology is revealing the complex role of the fibrotic stroma in pancreatic cancer pathogenesis and consider the therapeutic implications. Finally, we discuss critical gaps in our understanding and how we might better formulate strategies to successfully overcome the fibrotic barriers in pancreatic cancer.

DOI： 10.3390/cancers15030724

Web of Science

PubMed

【新しい技術で解明されてきた膵臓の病態】癌関連線維芽細胞の形質改変による抗癌剤効果増強剤の開発

飯田忠, 水谷泰之, 山雄健太郎, 石川卓哉, 大野栄三郎, 藤城光弘, 榎本篤, 川嶋啓揮

膵臓 Vol. 38 ( 1 ) page： 37 - 43 2023.2

Language：Japanese Publisher：(一社)日本膵臓学会

膵癌の特徴として間質の線維化とそれに伴う組織硬化がある.組織硬化は間質内圧上昇と血管虚脱を誘導し,その結果抗癌剤の間質浸透と癌細胞への到達を阻害することが知られている.この間質の線維化に中心的な役割を果たすのが癌関連線維芽細胞(CAF)である.このため,これまで様々な方法でCAFをターゲットにする治療が試みられてきたが未だ成功していない.本研究では癌抑制性CAFのマーカーであり機能分子であるMeflinをCAFに発現誘導することで,膵癌における化学療法への感受性を改善させることを明らかにした.さらにスクリーニングにより合成レチノイドであるAM80がCAFにおけるMeflinの発現を効果的に誘導し,ドラッグデリバリーの改善を伴って化学療法に対する感受性を改善させることを明らかにした.筆者らは本結果を受けて切除不能膵癌に対するAM80と従来の抗癌剤の併用効果を検証する医師主導治験を行っている.(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J02025&link_issn=&doc_id=20230308380005&doc_link_id=10.2958%2Fsuizo.38.37&url=https%3A%2F%2Fdoi.org%2F10.2958%2Fsuizo.38.37&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Novel Therapeutic Potentials of Taxifolin for Obesity-Induced Hepatic Steatosis, Fibrogenesis, and Tumorigenesis Reviewed

Takayuki Inoue, Bin Fu, Miwako Nishio, Miyako Tanaka, Hisashi Kato, Masashi Tanaka, Michiko Itoh, Hajime Yamakage, Kozue Ochi, Ayaka Ito, Yukihiro Shiraki, Satoshi Saito, Masafumi Ihara, Hideo Nishimura, Atsuhiko Kawamoto, Shian Inoue, Kumiko Saeki, Atsushi Enomoto, Takayoshi Suganami, Noriko Satoh-Asahara

Nutrients Vol. 15 ( 2 ) page： 350 - 350 2023.1

Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

The molecular pathogenesis of nonalcoholic steatohepatitis (NASH) includes a complex interaction of metabolic stress and inflammatory stimuli. Considering the therapeutic goals of NASH, it is important to determine whether the treatment can prevent the progression from NASH to hepatocellular carcinoma. Taxifolin, also known as dihydroquercetin, is a natural bioactive flavonoid with antioxidant and anti-inflammatory properties commonly found in various foods and health supplement products. In this study, we demonstrated that Taxifolin treatment markedly prevented the development of hepatic steatosis, chronic inflammation, and liver fibrosis in a murine model of NASH. Its mechanisms include a direct action on hepatocytes to inhibit lipid accumulation. Taxifolin also increased brown adipose tissue activity and suppressed body weight gain through at least two distinct pathways: direct action on brown adipocytes and indirect action via fibroblast growth factor 21 production in the liver. Notably, the Taxifolin treatment after NASH development could effectively prevent the development of liver tumors. Collectively, this study provides evidence that Taxifolin shows pleiotropic effects for the treatment of the NASH continuum. Our data also provide insight into the novel mechanisms of action of Taxifolin, which has been widely used as a health supplement with high safety.

DOI： 10.3390/nu15020350

Web of Science

PubMed

Wnt activation-induced disturbance of cell competition causes diffuse invasion of transformed cells through upregulation of NF-κB-mediated MMP21

Kazuki Nakai, Hancheng Lin, Shotaro Yamano, Shinya Tanaka, Sho Kitamoto, Kenta Sakuma, Junpei Kurauchi, Eilma Akter, Masamitsu Konno, Jun Koseki, Hirotaka Takahashi, Hideshi Yokoyama, Yukihiro Shiraki, Atsushi Enomoto, Sohei Abe, Yoku Hayakawa, Tetsuo Ushiku, Michihiro Mutoh, Yasuyuki Fujita, Shunsuke Kon

2022.12

Publisher：Research Square Platform LLC

Abstract

Normal epithelial cells exert their competitive advantage over RasV12-transformed cells and eliminate them into the apical lumen via cell competition. However, the internal or external factors that compromise cell competition and provoke carcinogenesis remains unknown. In this study, we examined the effect of sequential accumulation of gene mutations, mimicking multi-sequential carcinogenesis on RasV12-induced cell competition in intestinal epithelial tissues. Consequently, we found that directionality of RasV12-cell extrusion in Wnt-activated epithelia is reversed, and transformed cells are delaminated into the basal lamina via non-cell autonomous MMP21 upregulation. Subsequently, diffusively infiltrating, transformed cells develop into highly invasive carcinomas. Elevated production of MMP21 is elicited partly through NF-κB signaling, blockage of which restores apical elimination of RasV12 cells. We further found that the NF-κB-MMP21 axis is significantly bolstered in early colorectal carcinoma in humans. Collectively, this study shows that cells with high mutational burdens exploit cell competition for their benefit by behaving as unfit cells, endowing them with an invasion advantage.

DOI： 10.21203/rs.3.rs-2314559/v1

Other Link： https://www.researchsquare.com/article/rs-2314559/v1.html

Girdin Promotes Tumorigenesis and Chemoresistance in Lung Adenocarcinoma by Interacting with PKM2

Cao, FY; Yang, DS; Tang, FY; Lu, C; He, X; Chen, SM; Yang, ZH; Gong, SY; Sun, LQ; Enomoto, A; Takahashi, M; Weng, L

CANCERS Vol. 14 ( 22 ) 2022.11

Mammaglobin 1 mediates progression of trastuzumab-resistant breast cancer cells through regulation of cyclins and NF-κB. Reviewed International journal

Ratih Kusumastuti, Yuji Kumagai, Seiichiro Ishihara, Atsushi Enomoto, Takashi Murakami, Motoaki Yasuda, Hisashi Haga

FEBS open bio Vol. 12 ( 10 ) page： 1797 - 1813 2022.10

Language：English Publishing type：Research paper (scientific journal)

Overexpression of human epidermal growth factor receptor 2 (HER2) in various cancers is correlated with poor patient survival. Trastuzumab, a recombinant humanized monoclonal antibody against HER2, has been considered to be a first-line therapy for HER2-positive breast cancer patients, but its usefulness is limited by the development of resistance. In this study, we established resistant cells by long-term treatment with trastuzumab. These cells showed higher proliferation, invasion, and migration abilities than the wild-type cells. Mammaglobin 1 (MGB1), cyclin D1, E1, A2, and phosphorylated NF-κB (p-p65) were upregulated in resistant cells. These proteins regulate cell proliferation, migration, and invasion of resistant cells. Depletion of MGB1 decreased cyclin and p-p65 expression. Cyclin D1 and A2, but not E1 expression, were affected by p-p65 downregulation. In summary, our results indicate that MGB1 expression is increased in breast cancer cells that have gained resistance to trastuzumab, and suggest that MGB1 promotes aggressiveness through cyclin and NF-κB regulation.

DOI： 10.1002/2211-5463.13468

Web of Science

PubMed

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Papers - ENOMOTO, Atsushi