Faculty Profiles - ENOMOTO, Atsushi

Rikito Tatsuno, Jiro Ichikawa, Yoshihiro Komohara, Cheng Pan, Tomonori Kawasaki, Atsushi Enomoto, Kaoru Aoki, Keiko Hayakawa, Shintaro Iwata, Takahiro Jubashi, Hirotaka Haro

Cell Death & Disease Vol. 15 ( 2 ) page： 108 2024.2

TGF‐β signaling promotes desmoid tumor formation via CSRP2 upregulation Reviewed

Yu Li, Teruaki Fujishita, Emi Mishiro‐Sato, Yasushi Kojima, Yanqing Niu, Makoto Mark Taketo, Yuya Urano, Tomohisa Sakai, Atsushi Enomoto, Yoshihiro Nishida, Masahiro Aoki

Cancer Science Vol. 115 ( 2 ) page： 401 - 411 2024.2

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

Abstract

Desmoid tumors (DTs), also called desmoid‐type fibromatoses, are locally aggressive tumors of mesenchymal origin. In the present study, we developed a novel mouse model of DTs by inducing a local mutation in the Ctnnb1 gene, encoding β‐catenin in PDGFRA‐positive stromal cells, by subcutaneous injection of 4‐hydroxy‐tamoxifen. Tumors in this model resembled histologically clinical samples from DT patients and showed strong phosphorylation of nuclear SMAD2. Knockout of SMAD4 in the model significantly suppressed tumor growth. Proteomic analysis revealed that SMAD4 knockout reduced the level of Cysteine‐and‐Glycine‐Rich Protein 2 (CSRP2) in DTs, and treatment of DT‐derived cells with a TGF‐β receptor inhibitor reduced CSRP2 RNA levels. Knockdown of CSRP2 in DT cells significantly suppressed their proliferation. These results indicate that the TGF‐β/CSRP2 axis is a potential therapeutic target for DTs downstream of TGF‐β signaling.

DOI： 10.1111/cas.16037

Web of Science

PubMed

頭蓋内における間葉系幹細胞マーカーMeflinの発現解析(Expression of Meflin, a Mesenchymal Stem Cell(MSC) Marker, in the Intracranial Region)

白木之浩, 安藤良太, 三井伸二, 榎本篤

日本病理学会会誌 Vol. 113 ( 1 ) page： 439 - 439 2024.2

多発転移を伴う神経内分泌と微小乳頭癌の特徴を示す浸潤性乳癌(Invasive breast cancer showing neuroendocrine and micropapillary features with multiple metastases)

川崎朋範, 田島知明, 村松千左子, 川村隆三, 竹見祥大, 鈴木美穂, 市原周, 榎本篤, 永井宏和, 谷山清巳

日本病理学会会誌 Vol. 113 ( 1 ) page： 302 - 303 2024.2

膵星細胞(PSC)の形態と機能

安藤良太, 渡會蒼大, 白木之浩, 三井伸二, 榎本篤

日本病理学会会誌 Vol. 113 ( 1 ) page： 400 - 400 2024.2

難治性がん腫の克服を目指したがん微小環境を標的とする抗体薬物複合体の研究開発

江崎寛季, 安藤良太, 宮井雄基, 松山誠, 白木之浩, 三井伸二, 高橋雅英, 榎本篤

日本病理学会会誌 Vol. 113 ( 1 ) page： 400 - 400 2024.2

Meflin is a marker of pancreatic stellate cells involved in fibrosis and epithelial regeneration in the pancreas. Reviewed International journal

Ryota Ando, Yukihiro Shiraki, Yuki Miyai, Hiroki Shimizu, Kazuhiro Furuhashi, Shun Minatoguchi, Katsuhiro Kato, Akira Kato, Tadashi Iida, Yasuyuki Mizutani, Kisuke Ito, Naoya Asai, Shinji Mii, Nobutoshi Esaki, Masahide Takahashi, Atsushi Enomoto

The Journal of pathology Vol. 262 ( 1 ) page： 61 - 75 2024.1

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

Pancreatic stellate cells (PSCs) are stromal cells in the pancreas that play an important role in pancreatic pathology. In chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC), PSCs are known to get activated to form myofibroblasts or cancer-associated fibroblasts (CAFs) that promote stromal fibroinflammatory reactions. However, previous studies on PSCs were mainly based on the findings obtained using ex vivo expanded PSCs, with few studies that addressed the significance of in situ tissue-resident PSCs using animal models. Their contributions to fibrotic reactions in CP and PDAC are also lesser-known. These limitations in our understanding of PSC biology have been attributed to the lack of specific molecular markers of PSCs. Herein, we established Meflin (Islr), a glycosylphosphatidylinositol-anchored membrane protein, as a PSC-specific marker in both mouse and human by using human pancreatic tissue samples and Meflin reporter mice. Meflin-positive (Meflin+ ) cells contain lipid droplets and express the conventional PSC marker Desmin in normal mouse pancreas, with some cells also positive for Gli1, the marker of pancreatic tissue-resident fibroblasts. Three-dimensional analysis of the cleared pancreas of Meflin reporter mice showed that Meflin+ PSCs have long and thin cytoplasmic protrusions, and are localised on the abluminal side of vessels in the normal pancreas. Lineage tracing experiments revealed that Meflin+ PSCs constitute one of the origins of fibroblasts and CAFs in CP and PDAC, respectively. In these diseases, Meflin+ PSC-derived fibroblasts showed a distinctive morphology and distribution from Meflin+ PSCs in the normal pancreas. Furthermore, we showed that the genetic depletion of Meflin+ PSCs accelerated fibrosis and attenuated epithelial regeneration and stromal R-spondin 3 expression, thereby implying that Meflin+ PSCs and their lineage cells may support tissue recovery and Wnt/R-spondin signalling after pancreatic injury and PDAC development. Together, these data indicate that Meflin may be a marker specific to tissue-resident PSCs and useful for studying their biology in both health and disease. © 2023 The Pathological Society of Great Britain and Ireland.

DOI： 10.1002/path.6211

Web of Science

PubMed

Impact of elobixibat on liver tumors, microbiome, and bile acid levels in a mouse model of nonalcoholic steatohepatitis

Sugiyama, Y; Yamamoto, K; Honda, T; Kato, A; Muto, H; Yokoyama, S; Ito, T; Imai, N; Ishizu, Y; Nakamura, M; Asano, T; Enomoto, A; Zaitsu, K; Ishigami, M; Fujishiro, M; Kawashima, H

HEPATOLOGY INTERNATIONAL Vol. 17 ( 6 ) page： 1378 - 1392 2023.12

Wnt activation disturbs cell competition and causes diffuse invasion of transformed cells through NF-κB-MMP21 pathway

Nakai, K; Lin, HC; Yamano, S; Tanaka, S; Kitamoto, S; Saitoh, H; Sakuma, K; Kurauchi, J; Akter, E; Konno, M; Ishibashi, K; Kamata, R; Ohashi, A; Koseki, J; Takahashi, H; Yokoyama, H; Shiraki, Y; Enomoto, A; Abe, S; Hayakawa, Y; Ushiku, T; Mutoh, M; Fujita, Y; Kon, S

NATURE COMMUNICATIONS Vol. 14 ( 1 ) page： 7048 2023.11

Neuroendocrine neoplasms in the breast oncology field: dilemmas of nature and morphology

Kawasaki, T; Tashima, T; Enomoto, A; Ichikawa, J; Nagai, H; Muramatsu, C; Nakamura, Y; Kaira, K

FRONTIERS IN ENDOCRINOLOGY Vol. 14 page： 1216424 2023.11

Targeting hyaluronan-mediated motility receptor (HMMR) enhances response to androgen receptor signalling inhibitors in prostate cancer Reviewed International journal

Josephine A. Hinneh, Joanna L. Gillis, Chui Yan Mah, Swati Irani, Raj K. Shrestha, Natalie K. Ryan, Enomoto Atsushi, Zeyad D. Nassar, David J. Lynn, Luke A. Selth, Masashi Kato, Margaret M. Centenera, Lisa M. Butler

British Journal of Cancer Vol. 129 ( 8 ) page： 1350 - 1361 2023.10

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

Background: Resistance to androgen receptor signalling inhibitors (ARSIs) represents a major clinical challenge in prostate cancer. We previously demonstrated that the ARSI enzalutamide inhibits only a subset of all AR-regulated genes, and hypothesise that the unaffected gene networks represent potential targets for therapeutic intervention. This study identified the hyaluronan-mediated motility receptor (HMMR) as a survival factor in prostate cancer and investigated its potential as a co-target for overcoming resistance to ARSIs. Methods: RNA-seq, RT-qPCR and Western Blot were used to evaluate the regulation of HMMR by AR and ARSIs. HMMR inhibition was achieved via siRNA knockdown or pharmacological inhibition using 4-methylumbelliferone (4-MU) in prostate cancer cell lines, a mouse xenograft model and patient-derived explants (PDEs). Results: HMMR was an AR-regulated factor that was unaffected by ARSIs. Genetic (siRNA) or pharmacological (4-MU) inhibition of HMMR significantly suppressed growth and induced apoptosis in hormone-sensitive and enzalutamide-resistant models of prostate cancer. Mechanistically, 4-MU inhibited AR nuclear translocation, AR protein expression and subsequent downstream AR signalling. 4-MU enhanced the growth-suppressive effects of 3 different ARSIs in vitro and, in combination with enzalutamide, restricted proliferation of prostate cancer cells in vivo and in PDEs. Conclusion: Co-targeting HMMR and AR represents an effective strategy for improving response to ARSIs. [Figure not available: see fulltext.]

DOI： 10.1038/s41416-023-02406-8

Scopus

PubMed

腫瘍免疫微小環境の上流制御因子としてのがん関連線維芽細胞、そして臨床応用へ(Cancer-associated fibroblasts as upstream regulators of the tumor immune microenvironment and therapeutic application)

大脇貴之, 宮井雄基, 飯田忠, 赤松秀輔, 榎本篤

日本癌学会総会記事 Vol. 82回 page： 1499 - 1499 2023.9

骨肉腫微小環境における腫瘍関連マクロファージ由来ケモカインの働き

辰野力人, 市川二郎, 菰原義弘, 榎本篤, 川崎朋範, 波呂浩孝

日本整形外科学会雑誌 Vol. 97 ( 8 ) page： S1891 - S1891 2023.8

骨肉腫微小環境における腫瘍関連マクロファージ由来ケモカインの働き

辰野力人, 市川二郎, 菰原義弘, 榎本篤, 川崎朋範, 波呂浩孝

日本整形外科学会雑誌 Vol. 97 ( 8 ) page： S1891 - S1891 2023.8

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Papers - ENOMOTO, Atsushi