Faculty Profiles - ENOMOTO, Atsushi

Papers - ENOMOTO, Atsushi

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Stiff extracellular matrix activates the transcription factor ATF5 to promote the proliferation of cancer cells

Ishihara, S; Enomoto, A; Sakai, A; Iida, T; Tange, S; Kioka, N; Nukuda, A; Nagasato, AI; Yasuda, M; Tokino, T; Haga, H

ISCIENCE Vol. 28 ( 3 ) 2025.3

Novel cell-to-cell communications between macrophages and fibroblasts regulate obesity-induced adipose tissue fibrosis.

Kohda H, Tanaka M, Shichino S, Arakawa S, Komori T, Ito A, Wada E, Ochi K, Yuan X, Takeda T, Saiki A, Tatsuno I, Ikeda K, Miyai Y, Enomoto A, Morikawa Y, Shimizu S, Ueha S, Matsushima K, Ogawa Y, Suganami T

Diabetes 2025.3

Vitamin D derivatives inhibit mesenchymal transition of mesothelial cells and mitigate peritoneal dissemination of ovarian cancer

Fujita, K; Hayashi, M; Yoshihara, M; Nomura, S; Kitami, K; Miyamoto, E; Iyoshi, S; Mogi, K; Fujimoto, H; Uno, K; Kunishima, A; Yamakita, Y; Tomita, H; Tsutsumi, R; Sakamoto, R; Nagasawa, K; Masuo, Y; Nishiuchi, T; Shibata, K; Enomoto, A; Kajiyama, H

MEDICAL MOLECULAR MORPHOLOGY 2025.2

Superoxide dismutase 2 deficiency in mesenchymal stromal cells induces sympathetic denervation and functional impairment of brown adipose tissue. International journal

Yuya Urano, Shinji Mii, Shun Asai, Nobutoshi Esaki, Ryota Ando, Yukihiro Shiraki, Tadashi Iida, Katsuhiro Kato, Mika Hori, Yoshitaka Hayashi, Takahiko Shimizu, Atsushi Enomoto

Pathology international Vol. 75 ( 2 ) page： 69 - 81 2025.2

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

Brown adipose tissue (BAT) is an energy-consuming organ, and its functional dysregulation contributes to the development of metabolic diseases and obesity. BAT function is regulated by the sympathetic nervous system but declines with age, which is partly caused by reduced sympathetic nerve fibers innervating BAT. Thus far, the role of mesenchymal stromal/stem cells in age-related BAT dysfunction remains unknown. Here, we show that BAT dysfunction may be induced by a defect in the antioxidant capacity of stromal cells that localize in and around the nerve fibers (perineurial cells) of BAT. These cells express Meflin, a marker of mesenchymal stromal/stem cells. Specific deletion of the antioxidant enzyme superoxide dismutase 2 in Meflin-lineage cells caused sympathetic denervation and whitening of BAT and its functional impairment, as exemplified by a decline in the fat oxidation rate during the daytime. This phenotype was accompanied by overexpression of the neurorepulsive factor semaphorin 3A in perineurial cells. Notably, Meflin-deficient mice exhibited resistance to doxorubicin-induced BAT dysfunction. These results highlight the role of Meflin+ stromal cells, including perineurial cells, in maintaining BAT function and suggest that targeting BAT stromal cells provides a new avenue for improving BAT function.

DOI： 10.1111/pin.13503

Web of Science

PubMed

Neuro-mesenchymal interaction mediated by a β2 adrenergic-nerve growth factor feedforward loop promotes colorectal cancer progression. Reviewed International journal

Hiroki Kobayashi, Tadashi Iida, Yosuke Ochiai, Ermanno Malagola, Xiaofei Zhi, Ruth A White, Jin Qian, Feijing Wu, Quin T Waterbury, Ruhong Tu, Biyun Zheng, Jonathan S LaBella, Leah B Zamechek, Atsushi Ogura, Susan L Woods, Daniel L Worthley, Atsushi Enomoto, Timothy C Wang

Cancer discovery Vol. 15 ( 1 ) page： 202 - 226 2025.1

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

Cancer-associated fibroblasts (CAFs) and nerves, components of the tumor microenvironment, have each been shown to directly promote gastrointestinal cancers. However, it remains unknown whether these cells interact with each other to regulate cancer progression. We found that in colorectal cancer (CRC) norepinephrine induces ADRB2-dependent nerve growth factor (NGF) secretion from CAFs, which in turn increases intra-tumor sympathetic innervation and norepinephrine accumulation. Adrenergic stimulation accelerates CRC growth through ADRA2A/Gi-mediated activation of Yes-Associated Protein (YAP). NGF from CAFs directly enhances CRC cell growth via the PI3K/AKT pathway. Treatment with a tropomyosin receptor kinase (Trk) inhibitor decreased YAP and AKT activation and CRC progression in mice. In human CRC, high NGF expression is associated with the mesenchymal-like tumor subtype and poor patient survival. These findings suggest a central role for reciprocal CAF-nerve crosstalk in promoting CRC progression. Blocking this feedforward loop with a Trk inhibitor may represent a potential therapeutic approach for CRC.

DOI： 10.1158/2159-8290.CD-24-0287

Web of Science

PubMed

ALPK2 prevents cardiac diastolic dysfunction in heart failure with preserved ejection fraction. International journal

Tatsuya Yoshida, Satoya Yoshida, Kohei Inukai, Katsuhiro Kato, Yoshimitsu Yura, Tomoki Hattori, Kentaro Taki, Atsushi Enomoto, Koji Ohashi, Takahiro Okumura, Noriyuki Ouchi, Haruya Kawase, Nina Wettschureck, Stefan Offermanns, Toyoaki Murohara, Mikito Takefuji

FASEB journal : official publication of the Federation of American Societies for Experimental Biology Vol. 38 ( 22 ) page： e70192 2024.11

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

Protein phosphorylation, controlled by protein kinases, is central to regulating various pathophysiological processes, including cardiac systolic function. The dysregulation of protein kinase activity plays a significant role in the pathogenesis of cardiac systolic dysfunction. While cardiac contraction mechanisms are well documented, the mechanisms underlying cardiac diastole remain elusive. This gap persists owing to the historical focus on systolic dysfunction in heart failure research. Recently, heart failure with preserved ejection fraction (HFpEF), an age-related disease characterized by cardiac diastolic dysfunction, has emerged as a major public health concern. However, its underlying mechanism remains unclear. In this study, we investigated cardiac protein kinases by analyzing the gene expression of 518 protein kinases in human tissues. We identified alpha-kinase 2 (ALPK2) as a novel cardiac-specific atypical kinase and generated tamoxifen-inducible, cardiomyocyte-specific Alpk2-knockout mice and Alpk2-overexpressing mice. Alpk2 deficiency did not affect cardiac systolic dysfunction in the myocardial infarction model or the pressure-overload-induced heart failure model. Notably, cardiomyocyte-specific Alpk2 deficiency exacerbated cardiac diastolic dysfunction induced by aging and in the HFpEF model. Conversely, Alpk2 overexpression increased the phosphorylation of tropomyosin 1, a major regulator that binds myosin to actin, and mitigated cardiac stiffness in HFpEF. This study provides novel evidence that ALPK2 represents a potential therapeutic target for cardiac diastolic dysfunction in HFpEF and age-related cardiac impairments.

DOI： 10.1096/fj.202402103R

Web of Science

PubMed

Pulmonary metastases of a renal angiomyolipoma: A case report, with whole-exome sequencing analysis. Reviewed International journal

Yuki Sonoda, Masataka Hirasaki, Yoko Usami, Tomoaki Torigoe, Tomonori Kawasaki, Nobuyuki Suzuki, Yukihiro Shiraki, Atsushi Enomoto, Hiroki Imada, Yasutaka Baba

Radiology case reports Vol. 19 ( 11 ) page： 4963 - 4969 2024.11

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

We present a case of pulmonary metastasis originating from renal angiomyolipoma (AML), as evidenced by whole-exome sequencing (WES) analysis. Although AML predominantly arises in the kidneys, it can emerge in various body parts, making it important to distinguish between multicentric development and metastasis. However, previous studies have not distinguished between these conditions. Our case features an 82-year-old woman with a history of renal AML who presented with multiple, randomly distributed, bilateral pulmonary nodules of varying size and pure fat densities. The patient's condition followed a benign course over 10 years. Through WES, we discovered shared mutations in pulmonary lesions that were absent in the patient's blood, including a pathological mutation in TSC2, suggesting a metastatic origin from renal AML. Knowledge of the pulmonary manifestations of AML and their distinctive imaging findings can help radiologists and clinicians diagnose and manage patients with similar presentations.

DOI： 10.1016/j.radcr.2024.07.113

PubMed

Meflin/ISLR is a marker of adipose stem and progenitor cells in mice and humans that suppresses white adipose tissue remodeling and fibrosis. Reviewed International journal

Toshikazu Ishihara, Katsuhiro Kato, Kotaro Matsumoto, Miyako Tanaka, Akitoshi Hara, Yukihiro Shiraki, Hidenori Morisaki, Yuya Urano, Ryota Ando, Kisuke Ito, Shinji Mii, Nobutoshi Esaki, Kazuhiro Furuhashi, Mikito Takefuji, Takayoshi Suganami, Toyoaki Murohara, Atsushi Enomoto

Genes to cells : devoted to molecular & cellular mechanisms Vol. 29 ( 10 ) page： 902 - 920 2024.10

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

Identifying specific markers of adipose stem and progenitor cells (ASPCs) in vivo is crucial for understanding the biology of white adipose tissues (WAT). PDGFRα-positive perivascular stromal cells represent the best candidates for ASPCs. This cell lineage differentiates into myofibroblasts that contribute to the impairment of WAT function. However, ASPC marker protein(s) that are functionally crucial for maintaining WAT homeostasis are unknown. We previously identified Meflin as a marker of mesenchymal stem cells (MSCs) in bone marrow and tissue-resident perivascular fibroblasts in various tissues. We also demonstrated that Meflin maintains the undifferentiated status of MSCs/fibroblasts. Here, we show that Meflin is expressed in WAT ASPCs. A lineage-tracing experiment showed that Meflin+ ASPCs proliferate in the WAT of obese mice induced by a high-fat diet (HFD), while some of them differentiate into myofibroblasts or mature adipocytes. Meflin knockout mice fed an HFD exhibited a significant fibrotic response as well as increases in adipocyte cell size and the number of crown-like structures in WAT, accompanied by impaired glucose tolerance. These data suggested that Meflin expressed by ASPCs may have a role in reducing disease progression associated with WAT dysfunction.

DOI： 10.1111/gtc.13154

Web of Science

PubMed

Protein kinase N promotes cardiac fibrosis in heart failure by fibroblast-to-myofibroblast conversion. Reviewed International journal

Satoya Yoshida, Tatsuya Yoshida, Kohei Inukai, Katsuhiro Kato, Yoshimitsu Yura, Tomoki Hattori, Atsushi Enomoto, Koji Ohashi, Takahiro Okumura, Noriyuki Ouchi, Haruya Kawase, Nina Wettschureck, Stefan Offermanns, Toyoaki Murohara, Mikito Takefuji

Nature communications Vol. 15 ( 1 ) page： 7638 - 7638 2024.9

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

Chronic fibrotic tissue disrupts various organ functions. Despite significant advances in therapies, mortality and morbidity due to heart failure remain high, resulting in poor quality of life. Beyond the cardiomyocyte-centric view of heart failure, it is now accepted that alterations in the interstitial extracellular matrix (ECM) also play a major role in the development of heart failure. Here, we show that protein kinase N (PKN) is expressed in cardiac fibroblasts. Furthermore, PKN mediates the conversion of fibroblasts into myofibroblasts, which plays a central role in secreting large amounts of ECM proteins via p38 phosphorylation signaling. Fibroblast-specific deletion of PKN led to a reduction of myocardial fibrotic changes and cardiac dysfunction in mice models of ischemia-reperfusion or heart failure with preserved ejection fraction. Our results indicate that PKN is a therapeutic target for cardiac fibrosis in heart failure.

DOI： 10.1038/s41467-024-52068-0

Web of Science

PubMed

Tumor-associated fibrosis: a unique mechanism promoting ovarian cancer metastasis and peritoneal dissemination. Reviewed International journal

Hiroki Fujimoto, Masato Yoshihara, Raymond Rodgers, Shohei Iyoshi, Kazumasa Mogi, Emiri Miyamoto, Sae Hayakawa, Maia Hayashi, Satoshi Nomura, Kazuhisa Kitami, Kaname Uno, Mai Sugiyama, Yoshihiro Koya, Yoshihiko Yamakita, Akihiro Nawa, Atsushi Enomoto, Carmela Ricciardelli, Hiroaki Kajiyama

Cancer metastasis reviews Vol. 43 ( 3 ) page： 1037 - 1053 2024.9

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

Epithelial ovarian cancer (EOC) is often diagnosed in advanced stage with peritoneal dissemination. Recent studies indicate that aberrant accumulation of collagen fibers in tumor stroma has a variety of effects on tumor progression. We refer to remodeled fibrous stroma with altered expression of collagen molecules, increased stiffness, and highly oriented collagen fibers as tumor-associated fibrosis (TAF). TAF contributes to EOC cell invasion and metastasis in the intraperitoneal cavity. However, an understanding of molecular events involved is only just beginning to emerge. Further development in this field will lead to new strategies to treat EOC. In this review, we focus on the recent findings on how the TAF contributes to EOC malignancy. Furthermore, we will review the recent initiatives and future therapeutic strategies for targeting TAF in EOC.

DOI： 10.1007/s10555-024-10169-8

Web of Science

PubMed

進行卵巣癌でMeflin陽性癌関連線維芽細胞が腫瘍進展、生命予後に与える影響(Meflin-positive cancer-associated fibroblasts exhibit anti-tumor effects in advanced ovarian cancer)

宮本絵美里, 吉原雅人, 小屋美博, 藤本裕基, 伊吉祥平, 茂木一将, 宇野枢, 北見和久, 榎本篤, 梶山広明, 梶山広明

日本癌学会総会記事 Vol. 83回 page： E - 3056 2024.9

骨肉腫微小環境における腫瘍関連マクロファージ由来IL-8の働き

辰野力人, 市川二郎, 菰原義弘, 榎本篤, 川崎朋範, 重橋孝洋, 波呂浩孝

日本整形外科学会雑誌 Vol. 98 ( 8 ) page： S1968 - S1968 2024.9

Surface Markers and Chemokines/Cytokines of Tumor-Associated Macrophages in Osteosarcoma and Other Carcinoma Microenviornments-Contradictions and Comparisons. Reviewed International journal

Rikito Tatsuno, Yoshihiro Komohara, Cheng Pan, Tomonori Kawasaki, Atsushi Enomoto, Takahiro Jubashi, Hiroyuki Kono, Masanori Wako, Tomoyuki Ashizawa, Hirotaka Haro, Jiro Ichikawa

Cancers Vol. 16 ( 16 ) 2024.8

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

Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Prognosis is improving with advances in multidisciplinary treatment strategies, but the development of new anticancer agents has not, and improvement in prognosis for patients with pulmonary metastases has stalled. In recent years, the tumor microenvironment (TME) has gained attention as a therapeutic target for cancer. The immune component of OS TME consists mainly of tumor-associated macrophages (TAMs). They exhibit remarkable plasticity, and their phenotype is influenced by the TME. In general, surface markers such as CD68 and CD80 show anti-tumor effects, while CD163 and CD204 show tumor-promoting effects. Surface markers have potential value as diagnostic and prognostic biomarkers. The cytokines and chemokines produced by TAMs promote tumor growth and metastasis. However, the role of TAMs in OS remains unclear to date. In this review, we describe the role of TAMs in OS by focusing on TAM surface markers and the TAM-produced cytokines and chemokines in the TME, and by comparing their behaviors in other carcinomas. We found contrary results from different studies. These findings highlight the urgency for further research in this field to improve the stalled OS prognosis percentages.

DOI： 10.3390/cancers16162801

Web of Science

PubMed

Synthetic retinoid-mediated preconditioning of cancer-associated fibroblasts and macrophages improves cancer response to immune checkpoint blockade. Reviewed International journal

Takayuki Owaki, Tadashi Iida, Yuki Miyai, Katsuhiro Kato, Tetsunari Hase, Makoto Ishii, Ryota Ando, Kunihiko Hinohara, Tomohiro Akashi, Yasuyuki Mizutani, Takuya Ishikawa, Shinji Mii, Yukihiro Shiraki, Nobutoshi Esaki, Masami Yamamoto, Tetsuya Tsukamoto, Sachiyo Nomura, Takashi Murakami, Masahide Takahashi, Yuri Yuguchi, Motohiro Maeda, Tomoyasu Sano, Naoto Sassa, Yoshihisa Matsukawa, Hiroki Kawashima, Shusuke Akamatsu, Atsushi Enomoto

British journal of cancer Vol. 131 ( 2 ) page： 372 - 386 2024.7

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

BACKGROUND: The proliferation of cancer-associated fibroblasts (CAFs) hampers drug delivery and anti-tumor immunity, inducing tumor resistance to immune checkpoint blockade (ICB) therapy. However, it has remained a challenge to develop therapeutics that specifically target or modulate CAFs. METHODS: We investigated the involvement of Meflin+ cancer-restraining CAFs (rCAFs) in ICB efficacy in patients with clear cell renal cell carcinoma (ccRCC) and urothelial carcinoma (UC). We examined the effects of Am80 (a synthetic retinoid) administration on CAF phenotype, the tumor immune microenvironment, and ICB efficacy in cancer mouse models. RESULTS: High infiltration of Meflin+ CAFs correlated with ICB efficacy in patients with ccRCC and UC. Meflin+ CAF induction by Am80 administration improved ICB efficacy in the mouse models of cancer. Am80 exerted this effect when administered prior to, but not concomitant with, ICB therapy in wild-type but not Meflin-deficient mice. Am80-mediated induction of Meflin+ CAFs was associated with increases in antibody delivery and M1-like tumor-associated macrophage (TAM) infiltration. Finally, we showed the role of Chemerin produced from CAFs after Am80 administration in the induction of M1-like TAMs. CONCLUSION: Our data suggested that Am80 administration prior to ICB therapy increases the number of Meflin+ rCAFs and ICB efficacy by inducing changes in TAM phenotype.

DOI： 10.1038/s41416-024-02734-3

Web of Science

PubMed

Correction: Pivotal role of IL-8 derived from the interaction between osteosarcoma and tumor-associated macrophages in osteosarcoma growth and metastasis via the FAK pathway.

Tatsuno R, Ichikawa J, Komohara Y, Pan C, Kawasaki T, Enomoto A, Aoki K, Hayakawa K, Iwata S, Jubashi T, Haro H

Cell death & disease Vol. 15 ( 7 ) page： 471 2024.7

宮井雄基, 白木之浩, 安藤良太, 榎本篤

実験医学 Vol. 42 ( 11 ) page： 1684 - 1690 2024.7

Language：Japanese Publisher：(株)羊土社

がん関連線維芽細胞(CAF)はがん促進性の機能をもつと長く認識されてきた.一方で,CAFを除去あるいはその増殖を抑制するとがんの増悪が観察されたことから,CAFにはがん抑制性の機能があることも指摘されている.昨今の解析技術の発展により,CAFの多様性やその臨床的意義に関する理解は得られつつあるが,依然,がん抑制性CAFの本態は不明確である.本稿では,がん抑制性CAFに対する理解の現状と難しさについて,われわれの仮説も交えつつ概説したい.(著者抄録)

非浸潤性乳管癌に対する乳房温存術後の放射線照射は省略できるか? Reviewed

市原周, 伊藤典子, 森谷鈴子, 岩越朱里, 森田孝子, 大岩幹直, 佐久間貴彦, 中井登紀子, 窪田智行, 水谷三浩, 稲田健一, 川崎朋範, 榎本篤

現代医学 Vol. 71 ( 1 ) page： 104 - 109 2024.6

非浸潤性乳管癌に対する乳房温存術後の放射線照射は省略できるか?

市原周, 伊藤典子, 森谷鈴子, 岩越朱里, 森田孝子, 大岩幹直, 佐久間貴彦, 中井登紀子, 窪田智行, 水谷三浩, 稲田健一, 川崎朋範, 榎本篤

現代医学 Vol. 71 ( 1 ) page： 104 - 109 2024.6

Successful Treatment of Multiple Systemic Artery-to-Pulmonary Artery Fistulas.

Ryo T, Shigemitsu K, Mori S, Enomoto A, Chen-Yoshikawa TF

Annals of thoracic surgery short reports Vol. 2 ( 2 ) page： 172 - 174 2024.6

侵襲性微小乳頭所見と多発リンパ節転移を示す乳房神経内分泌腫瘍(Neuroendocrine tumor of the breast showing invasive micropapillary features and multiple lymph node metastases)

川崎朋範, 田島知明, 村松千左子, 藤本章博, 児玉ひとみ, 市川二郎, 永井宏和, 星田義彦, 谷山清巳, 榎本篤, 川村隆三, 竹見祥大, 鈴木美穂, 村松孝洋, 地主龍平, 宇佐見陽子, 中村泰大, 解良恭一

日本内分泌学会雑誌 Vol. 99 ( 5 ) page： 1674 - 1674 2024.4

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Papers - ENOMOTO, Atsushi