Faculty Profiles - ENOMOTO, Atsushi

Papers - ENOMOTO, Atsushi

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BMP3b is a Novel Anti-Fibrotic Molecule Regulated by Meflin in Lung Fibroblasts. Reviewed International journal

Atsushi Suzuki, Koji Sakamoto, Yoshio Nakahara, Atsushi Enomoto, Jun Hino, Akira Ando, Masahide Inoue, Yukihiro Shiraki, Norihito Omote, Masahiro Kusaka, Jun Fukihara, Naozumi Hashimoto

American journal of respiratory cell and molecular biology Vol. 67 ( 4 ) page： 446 - 458 2022.10

Language：English Publishing type：Research paper (scientific journal) Publisher：American Thoracic Society

Fibroblasts play a central role in the lung fibrotic process. Our recent study identified a novel subpopulation of lung fibroblasts expressing meflin, anti-fibrotic properties of which were confirmed by murine lung fibrosis model. Meflin expressing fibroblasts were resistant to fibrogenesis induced by transforming growth factor-β (TGF-β), but its underlying mechanisms remain unknown. In this study, evaluation of a silica-nanoparticles-induced lung fibrosis model confirmed the antifibrotic effect of meflin via the regulation of TGF-β signaling. We conducted comparative gene expression profiling in lung fibroblasts, which identified growth differentiation factor 10 (Gdf10) encoding bone morphogenic protein 3b (BMP3b) as the most down-regulated gene in meflin-deficient cells under the profibrotic condition with TGF-β. We hypothesized that BMP3b can be an effector molecule playing an anti-fibrotic role downstream of meflin. As suggested by single-cell transcriptomic data, restricted expressions of Gdf10 (Bmp3b) in stromal cells including fibroblasts were confirmed. We examined possible anti-fibrotic properties of BMP3b in lung fibroblasts and demonstrated that Bmp3b-null fibroblasts were more susceptible to TGF-β-induced fibrogenic changes. Furthermore, Bmp3b-null mice exhibited exaggerated lung fibrosis induced by silica-nanoparticles in vivo. We also demonstrated that treatment with recombinant BMP3B was effective against TGF-β-induced fibrogenesis in fibroblasts, especially in the suppression of excessive extracellular matrix production. These lines of evidence suggested that BMP3b is a novel humoral effector molecule regulated by meflin which exerts anti-fibrotic properties in lung fibroblasts. Supplementation of BMP3B could be a novel therapeutic strategy for fibrotic lung diseases.

DOI： 10.1165/rcmb.2021-0484OC

Web of Science

PubMed

Insulinoma-associated protein 1 (INSM1) expression in breast carcinomas with neuroendocrine morphologies: application and future perspectives

Kawasaki, T; Tashima, T; Ryozawa, S; Nakamura, Y; Fujimoto, A; Usami, Y; Inozume, T; Saitoh, M; Kondo, T; Enomoto, A; Nagai, H; Taniyama, K; Muramatsu, C; Kaira, K

HISTOPATHOLOGY Vol. 81 page： 31 - 31 2022.10

【免疫チェックポイント阻害薬の"耐性"に挑むがん免疫サイクルから見出す戦略】がん間質の線維芽細胞・腫瘍血管と免疫チェックポイント阻害薬の耐性機構

榎本篤, 宮井雄基, 飯田忠, 大脇貴之

実験医学 Vol. 40 ( 16 ) page： 2580 - 2586 2022.10

Language：Japanese Publisher：(株)羊土社

ヒトのがんの間質の免疫細胞の浸潤、線維化、および腫瘍血管の増生の程度はがんの種類あるいは症例間で実に多様である。同一症例の標本でも視野を少し動かしただけで、同じがんとは思えないような組織像の違いを見せることもある。免疫チェックポイント阻害薬(ICI)の勃興によりがん治療の概念が変わり、それに伴いヒト免疫学も飛躍的に発展したと聞く。しかしながら、一部の特殊なゲノム異常を有するがんを除き、前述の腫瘍内(intratumor)および腫瘍間(intertumor)の多様性がICIの奏功予測や一律な奏効率の押し上げを困難なものにしていると推測される。本稿では、主に線維芽細胞と腫瘍血管に焦点をあて、これらが抗腫瘍免疫応答およびICIの効果に及ぼす影響、およびその知見に基づく治療戦略について概説したい。(著者抄録)

骨肉腫におけるMeflin陽性細胞を標的とした抗体薬物複合体の研究開発(An Effective Therapy that Antibody-Drug Conjugates Targeting Meflin(+) Cells for Osteosarcoma)

迫田朋佳, 江崎寛季, 安藤良太, 宮井雄基, 飯田忠, 松山誠, 白木之浩, 三井伸二, 西田佳弘, 高橋雅英, 榎本篤

日本癌学会総会記事 Vol. 81回 page： E - 2021 2022.9

腫瘍促進的腹膜環境の正常化を標的とした難治性卵巣癌に対する新規治療戦略の開発(Peritoneal restoration by repurposing vitamin D inhibits ovarian cancer dissemination via blockade of TGF-β1/THBS1)

北見和久, 吉原雅人, 山北由彦, 杉山麻衣, 小屋美博, 宮本絵美里, 藤本裕基, 伊吉祥平, 宇野枢, 茂木一将, 加藤一喜, 那波明宏, 榎本篤, 梶山広明

日本癌学会総会記事 Vol. 81回 page： MS1 - 3 2022.9

癌抑制性線維芽細胞の同定と治療応用(Identification of tumor suppressor fibroblasts and therapeutic applications)

飯田忠, 水谷泰之, 川嶋啓揮, 榎本篤

日本癌学会総会記事 Vol. 81回 page： J - 3026 2022.9

Meflinは尿路上皮癌における免疫チェックポイント阻害剤治療の効果予測バイオマーカーである(Meflin is a good predictive biomarker for ICI in urothelial carcinoma)

大脇貴之, 宮井雄基, 飯田忠, 江崎寛季, 白木之浩, 三井伸二, 榎本篤

日本癌学会総会記事 Vol. 81回 page： P - 2185 2022.9

Possible disease-protective roles of fibroblasts in cancer and fibrosis and their therapeutic application Reviewed

Shiraki, Yukihiro, Mii, Shinji, Esaki, Nobutoshi, Enomoto, Atsushi

Vol. 84 ( 3 ) page： 484 - 496 2022.8

【膵臓の発生・生理・解剖から膵炎・膵癌の病態解明に至る最新の知見】がん抑制性線維芽細胞の本態の理解とその治療応用について

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

胆と膵 Vol. 43 ( 8 ) page： 787 - 794 2022.8

Language：Japanese Publisher：医学図書出版(株)

膵癌治療のボトルネックは、その豊富な間質に起因する薬剤送達(drug delivery)の障害であり、これを解決する治療法の開発が強く求められている。膵癌の豊富な間質の原因は、がん関連線維芽細胞(CAF)の増生であり、がんを促進する形質を有することから治療標的として注目されて久しい。しかしながら、線維芽細胞の活性化および増殖を阻害する薬剤を臨床応用する試みはうまくいっていない。それらの結果より近年では、線維芽細胞はがん促進性と抑制性の二つの極性(性質の連続的な差異)を有していること、さらに同細胞の極性はがん発育の文脈に沿って容易に変換されることの2点が原因であると考えられるようになった。われわれは最近、meflin陽性線維芽細胞が、がん抑制性線維芽細胞であり、その機能は従来の活性化線維芽細胞(筋線維芽細胞やCAF)とは異なっていること、および、線維芽細胞の極性を制御することで抗がん剤の送達性の向上が図れることをマウスモデルで示してきた。これらの知見をベースに、現在、われわれは線維芽細胞の極性の変化を誘導する薬剤の効果を検証する医師主導治験を行っている。(著者抄録)

Efficacy of auranofin as an inhibitor of desmoid progression. Reviewed International journal

Kan Ito, Yoshihiro Nishida, Shunsuke Hamada, Koki Shimizu, Tomohisa Sakai, Bisei Ohkawara, Benjamin A Alman, Atsushi Enomoto, Kunihiro Ikuta, Hiroshi Koike, Jiarui Zhang, Kinji Ohno, Shiro Imagama

Scientific reports Vol. 12 ( 1 ) page： 11918 - 11918 2022.7

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

Anticancer drugs and molecular targeted therapies are used for refractory desmoid-type fibromatosis (DF), but occasionally cause severe side effects. The purpose of this study was to identify an effective drug with fewer side effects against DF by drug repositioning, and evaluate its efficacy. FDA-approved drugs that inhibit the proliferation of DF cells harboring S45F mutations of CTNNB1 were screened. An identified drug was subjected to the investigation of apoptotic effects on DF cells with analysis of Caspase 3/7 activity. Expression of β-catenin was evaluated with western blot analysis, and immunofluorescence staining. Effects of the identified drug on in vivo DF were analyzed using Apc1638N mice. Auranofin was identified as a drug that effectively inhibits the proliferation of DF cells. Auranofin did not affect Caspase 3/7 activity compared to control. The expression level of β-catenin protein was not changed regardless of auranofin concentration. Auranofin effectively inhibited the development of tumorous tissues by both oral and intraperitoneal administration, particularly in male mice. Auranofin, an anti-rheumatic drug, was identified to have repositioning effects on DF. Since auranofin has been used for many years as an FDA-approved drug, it could be a promising drug with fewer side effects for DF.

DOI： 10.1038/s41598-022-15756-9

Web of Science

PubMed

Recurrent fulminant non-rheumatic streptococcal myocarditis proven by endomyocardial biopsy and autopsy. Reviewed

Hiroaki Hiraiwa, Ryota Morimoto, Ryota Ando, Ryota Ito, Takashi Araki, Takashi Mizutani, Shingo Kazama, Yuki Kimura, Hideo Oishi, Tasuku Kuwayama, Shogo Yamaguchi, Toru Kondo, Takahiro Okumura, Atsushi Enomoto, Toyoaki Murohara

Journal of cardiology cases Vol. 26 ( 1 ) page： 62 - 65 2022.7

Language：English

A 42-year-old man with a history of acute myocarditis after streptococcal pharyngitis developed recurrent fulminant myocarditis. Endomyocardial biopsy revealed myocyte degeneration, interstitial edema, and neutrophil infiltration. The patient's cardiac function deteriorated rapidly, and he died despite mechanical circulatory support. Autopsy revealed neutrophil infiltration, interstitial edema, and micro-abscesses containing masses of streptococci and neutrophilic phagocytosis within the myocardium. The patient did not meet the diagnostic criteria for acute rheumatic fever; thus, he was diagnosed with non-rheumatic streptococcal myocarditis. Non-rheumatic streptococcal myocarditis rarely recurs, but it can be fulminant upon recurrence. Learning objective: We report a rare case of recurrent fulminant non-rheumatic streptococcal myocarditis. Endomyocardial biopsy and autopsy revealed neutrophil infiltration and micro-abscesses containing bacterial masses of streptococci and neutrophilic phagocytosis in the myocardium. The patient did not meet the diagnostic criteria for acute rheumatic fever; thus, he was diagnosed with non-rheumatic streptococcal myocarditis. Non-rheumatic streptococcal myocarditis rarely recurs, but it can be fulminant upon recurrence.

DOI： 10.1016/j.jccase.2022.02.004

PubMed

Good and Bad Stroma in Pancreatic Cancer: Relevance of Functional States of Cancer-Associated Fibroblasts. Reviewed International journal

Ryota Ando, Akihiro Sakai, Tadashi Iida, Kunio Kataoka, Yasuyuki Mizutani, Atsushi Enomoto

Cancers Vol. 14 ( 14 ) 2022.7

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

A well-known feature of human pancreatic ductal adenocarcinoma (PDAC) is the extensive proliferation of cancer-associated fibroblasts (CAFs) and highly fibrotic stroma. Recent evidence, based mainly on single-cell analyses, has identified various subsets of CAFs in PDAC mouse models. However, we do not know how these CAF subsets are involved in the progression and drug resistance of human PDAC. Additionally, it remains unclear whether these diverse CAFs have distinct origins and are indicators of genuinely distinct CAF lineages or reflect different states of the same CAFs depending on the tumor microenvironment. Interestingly, recent preclinical studies have started to characterize the nature of cancer-restraining CAFs and have identified their markers Meflin and collagen type I alpha 1. These studies have led to the development of strategies to induce changes in CAF phenotypes using chemical reagents or recombinant viruses, and some of them have been tested in clinical studies. These strategies have the unique potential to convert the so-called bad stroma to good stroma and may also have therapeutic implications for non-cancer diseases such as fibrotic diseases. Together with recently developed sophisticated strategies that specifically target distinct CAF subsets via adoptive cell transfer therapy, vaccination, and antibody-drug conjugates, any future findings arising from these clinical efforts may expand our understanding of the significance of CAF diversity in human PDAC.

DOI： 10.3390/cancers14143315

Web of Science

PubMed

Correction: Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to chemotherapeutics. Reviewed International journal

Tadashi Iida, Yasuyuki Mizutani, Nobutoshi Esaki, Suzanne M Ponik, Brian M Burkel, Liang Weng, Keiko Kuwata, Atsushi Masamune, Seiichiro Ishihara, Hisashi Haga, Kunio Kataoka, Shinji Mii, Yukihiro Shiraki, Takuya Ishikawa, Eizaburo Ohno, Hiroki Kawashima, Yoshiki Hirooka, Mitsuhiro Fujishiro, Masahide Takahashi, Atsushi Enomoto

Oncogene Vol. 41 ( 23 ) page： 3302 - 3302 2022.6

Spindle Cell Lipoma with Ossification Mimicking Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma: A Case Report. Reviewed International journal

Jiro Ichikawa, Tomonori Kawasaki, Hiroki Imada, Atsushi Enomoto, Naofumi Taniguchi, Rikito Tatsuno, Satoshi Kanno, Hirotaka Haro

International journal of surgical pathology Vol. 30 ( 4 ) page： 413 - 418 2022.6

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

Although spindle cell lipoma (SCL) is a subtype of lipoma, the characteristics of SCL are observed in both lipomatous and non-lipomatous tumors. In this article, we present a case of SCL with ossification mimicking atypical lipomatous tumors/well-differentiated liposarcomas (ALTs/WDLs). Considering the findings of magnetic resonance imaging and needle biopsy, which exhibited ALTs/WDLs, marginal resection was performed. Histopathological findings demonstrated mature adipocytes and spindle cells without atypia and no malignant osteoid tissue in the ossified region. In addition, immunohistochemistry (IHC) showed positive staining for CD34, heterogeneous retinoblastoma protein deficiency, and negative staining for mouse double minute 2 homolog (MDM2) and cyclin-dependent kinase. Fluorescence in-situ hybridization showed negative amplification of MDM2. The final diagnosis of the tumor was established using IHC as an extremely rare SCL with ossification.

DOI： 10.1177/10668969211055798

Web of Science

PubMed

Letter to Editor Regarding "Nuclear Insulinoma-Associated Protein 1 Expression as a Marker of Neuroendocrine Differentiation in Neoplasms of the Breast" by Seijnhaeve et al. Reviewed International journal

Tomonori Kawasaki, Tomoaki Tashima, Yasuhiro Nakamura, Tetsuo Kondo, Atsushi Enomoto, Kyoichi Kaira

International journal of surgical pathology Vol. 30 ( 4 ) page： 470 - 471 2022.6

The interferon-β/STAT1 axis drives the collective invasion of skin squamous cell carcinoma with sealed intercellular spaces. Reviewed International journal

Yuji Kumagai, Junko Nio-Kobayashi, Seiichiro Ishihara, Atsushi Enomoto, Masashi Akiyama, Ryosuke Ichihara, Hisashi Haga

Oncogenesis Vol. 11 ( 1 ) page： 27 - 27 2022.5

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

The process by which cancer cells invade as a cell cluster, known as collective invasion, is associated with metastasis and worse prognosis of cancer patients; therefore, inhibition of collective invasion is considered to improve cancer treatment. However, the cellular characteristics responsible for collective invasion remain largely unknown. Here, we successfully established subclones with various invasive potentials derived from human skin squamous carcinoma cells. The cell cluster of the highly invasive subclone had a hermetically sealed and narrow intercellular space. Interferon-β was localized to the sealed intercellular spaces, leading to collective invasion via the activation of signal transducer and activator of transcription 1 (STAT1). On the other hand, interferon-β was not localized to non-sealed and wide intercellular spaces of the cell cluster of low-invasive subclone with deficient STAT1 activity. In the mixed cell cluster of high- and low-invasive subclones, the high-invasive sub-clonal cells were located at the invasive front of the invasive protrusion, leading to collective invasion by the low-invasive sub-clonal cells. Tissue microarray analysis of human skin squamous cell carcinoma (SCC) also showed enrichment of STAT1 in the invasive front of SCCs. These findings indicate that the intercellular structure controls the potential for collective invasion via STAT1 regulation in SCC.

DOI： 10.1038/s41389-022-00403-9

Web of Science

PubMed

Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to chemotherapeutics. Reviewed International journal

Oncogene Vol. 41 ( 19 ) page： 2764 - 2777 2022.5

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Previous therapeutic attempts to deplete cancer-associated fibroblasts (CAFs) or inhibit their proliferation in pancreatic ductal adenocarcinoma (PDAC) were not successful in mice or patients. Thus, CAFs may be tumor suppressive or heterogeneous, with distinct cancer-restraining and -promoting CAFs (rCAFs and pCAFs, respectively). Here, we showed that induced expression of the glycosylphosphatidylinositol-anchored protein Meflin, a rCAF-specific marker, in CAFs by genetic and pharmacological approaches improved the chemosensitivity of mouse PDAC. A chemical library screen identified Am80, a synthetic, nonnatural retinoid, as a reagent that effectively induced Meflin expression in CAFs. Am80 administration improved the sensitivity of PDAC to chemotherapeutics, accompanied by increases in tumor vessel area and intratumoral drug delivery. Mechanistically, Meflin was involved in the suppression of tissue stiffening by interacting with lysyl oxidase to inhibit its collagen crosslinking activity. These data suggested that modulation of CAF heterogeneity may represent a strategy for PDAC treatment.

DOI： 10.1038/s41388-022-02288-9

Web of Science

PubMed

The Critical Role of Meflin-Positive Fibroblasts Against Acute Lung Injury

Hashimoto, N; Sakamoto, K; Nakahara, Y; Omote, N; Ando, A; Inoue, M; Suzuki, A; Fukihara, J; Kusaka, M; Wakahara, K; Enomoto, A

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Vol. 205 2022.5

Meflin-BMP3b Axis Is a Novel Anti-Fibrotic Pathway Against TGF-β-Induced Lung Fibrogenesis

Suzuki, A; Sakamoto, K; Nakahara, Y; Enomoto, A; Hino, J; Ando, A; Inoue, M; Omote, N; Kusaka, M; Fukihara, J; Hashimoto, N

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Vol. 205 2022.5

Peritoneal restoration by repurposing vitamin D inhibits ovarian cancer dissemination via blockade of the TGF-β1/thrombospondin-1 axis. Reviewed International journal

Kazuhisa Kitami, Masato Yoshihara, Satoshi Tamauchi, Mai Sugiyama, Yoshihiro Koya, Yoshihiko Yamakita, Hiroki Fujimoto, Shohei Iyoshi, Kaname Uno, Kazumasa Mogi, Yoshiki Ikeda, Akira Yokoi, Nobuhisa Yoshikawa, Kimihiro Nishino, Kaoru Niimi, Akihiro Nawa, Atsushi Enomoto, Hiroaki Kajiyama

Matrix biology : journal of the International Society for Matrix Biology Vol. 109 page： 70 - 90 2022.5

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

Ovarian cancer (OvCa), a lethal gynecological malignancy, disseminates to the peritoneum. Mesothelial cells (MCs) act as barriers in the abdominal cavity, preventing the adhesion of cancer cells. However, in patients with OvCa, they are transformed into cancer-associated mesothelial cells (CAMs) via mesenchymal transition and form a favorable microenvironment for tumors to promote metastasis. However, attempts for restoring CAMs to their original state have been limited. Here, we investigated whether inhibition of mesenchymal transition and restoration of MCs by vitamin D suppressed the OvCa dissemination in vitro and in vivo. The effect of vitamin D on the mutual association of MCs and OvCa cells was evaluated using in vitro coculture models and in vivo using a xenograft model. Vitamin D restored the CAMs, and thrombospondin-1 (component of the extracellular matrix that is clinically associated with poor prognosis and is highly expressed in peritoneally metastasized OvCa) was found to promote OvCa cell adhesion and proliferation. Mechanistically, TGF-β1 secreted from OvCa cells enhanced thrombospondin-1 expression in CAMs via Smad-dependent TGF-β signaling. Vitamin D inhibited mesenchymal transition in MCs and suppressed thrombospondin-1 expression via vitamin D receptor/Smad3 competition, contributing to the marked reduction in peritoneal dissemination in vivo. Importantly, vitamin D restored CAMs from a stabilized mesenchymal state to the epithelial state and normalized thrombospondin-1 expression in preclinical models that mimic cancerous peritonitis in vivo. MCs are key players in OvCa dissemination and peritoneal restoration and normalization of thrombospondin-1 expression by vitamin D may be a novel strategy for preventing OvCa dissemination.

DOI： 10.1016/j.matbio.2022.03.003

Web of Science

PubMed

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Papers - ENOMOTO, Atsushi