Faculty Profiles - ENOMOTO, Atsushi

Papers - ENOMOTO, Atsushi

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Significance of meflin-positive cancer-associated fibroblasts in predicting response to immune checkpoint inhibitors in non-small cell lung cancer.

Miyai, Y; Enomoto, A; Ando, Y; Takahashi, M

JOURNAL OF CLINICAL ONCOLOGY Vol. 38 ( 15 ) 2020.5

Significance of meflin-positive cancer-associated fibroblasts in predicting response to immune checkpoint inhibitors in non-small cell lung cancer.

Yuki Miyai, Atsushi Enomoto, Yuichi Ando, Masahide Takahashi

Journal of Clinical Oncology Vol. 38 ( 15_suppl ) page： 3118 - 3118 2020.5

Publishing type：Research paper (scientific journal) Publisher：American Society of Clinical Oncology (ASCO)

3118

Background: Tumor immunity is regulated by complex interactions between cancer and immune cells, which also involves other components of the tumor microenvironment (TME). Recently, cancer-associated fibroblasts (CAFs), a major constituent of the TME, have emerged as important regulators of tumor immunity. Specifically, for example, α-smooth muscle actin or leucine-rich repeat containing 15-positive CAFs have been shown to be crucial for the suppression of tumor immunity. However, a comprehensive picture of how other CAF subset(s) are involved in tumor immunity is still lacking. Here, we show the involvement of a CAF subset highly expressing Meflin, which was recently identified as a marker of cancer-restraining CAFs in pancreatic cancer (Mizutani et al., Cancer Res, 2019), in the response of non-small cell lung cancer (NSCLC) patients to immune checkpoint inhibitors (ICIs). Methods: A sample cohort of 122 subjects with NSCLC who had received ICI monotherapy with nivolumab, pembrolizumab, or atezolizumab was identified at the Department of Respiratory Medicine at Nagoya University Hospital. We selected 92 eligible patients, collected formalin-fixed paraffin-embedded tumor tissues, and prepared 4–µm-thick slides for the analysis of Meflin expression by RNA-in situ hybridization assay, followed by the evaluation of treatment response of 88 patients using the iRECIST criteria. We assessed the number of Meflin-positive CAFs and divided the patients into Meflin-High (20% and more CAFs express Meflin) and -Low groups. The cut-off value was obtained by the ROC analysis. Primarily, objective response rate (ORR) was compared between Meflin-High and –Low groups. Overall survival (OS), and progression free survival (PFS) were also assessed. Results: Patients who started to receive ICIs till the end of March 2019 were enrolled and followed-up until the end of 2019. Analysis of the tumor tissues revealed that 24 (40.7%) of 59 Meflin-High patients responded to the ICI monotherapy. In contrast, none (0%) of 29 Meflin-Low patients showed any significant response (p-value: 0.0000174). Meflin-High groups showed statistically significant prolongations in both OS and PFS with the hazard ratios of 0.3114 [0.1591-0.6094] and 0.3997 [0.2290-0.6976], respectively. Conclusions: This retrospective observation indicated that the high infiltration of Meflin-positive CAFs may shape tumor-suppressive immune response and increase the sensitivity to ICIs, which differs from those of other CAF subsets.

DOI： 10.1200/jco.2020.38.15_suppl.3118

Cancer-associated fibroblasts that restrain cancer progression: Hypotheses and perspectives. Reviewed International journal

Yuki Miyai, Nobutoshi Esaki, Masahide Takahashi, Atsushi Enomoto

Cancer science Vol. 111 ( 4 ) page： 1047 - 1057 2020.4

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

The roles of cancer-associated fibroblasts (CAF) in the progression of various types of cancers are well established. CAF promote cancer progression through pleiotropic mechanisms, including the secretion of soluble factors and extracellular matrix, physical interactions with cancer cells, and the regulation of angiogenesis, immunity and metabolism. Their contribution to therapeutic resistance is also well appreciated. Therefore, CAF have been considered as a therapeutic target in cancer. However, recent studies in autochthonous pancreatic cancer models suggest that specific subset(s) of CAF exhibit cancer-restraining roles, indicating that CAF are functionally and molecularly heterogeneous, which is supported by recent single-cell transcriptome analyses. While cancer-promoting CAF (pCAF) have been extensively studied, the nature and specific marker(s) of cancer-restraining CAF (rCAF) have remained uncharacterized. Interestingly, a recent study provided insight into the nature of rCAF and suggested that they may share molecular properties with pancreatic stellate cells (PSC) and mesenchymal stem/stromal cells (MSC). Complicating this finding is that PSC and MSC have been shown to promote the formation of a tumor-permissive and tumor-promoting environment in xenograft tumor models. However, these cells undergo significant transcriptional and epigenetic changes during ex vivo culture, which confounds the interpretation of experimental results based on the use of cultured cells. In this short review, we describe recent studies and hypotheses on the identity of rCAF and discuss their analogy to fibroblasts that suppress fibrosis in fibrotic diseases. Finally, we discuss how these findings can be exploited to develop novel anticancer therapies in the future.

DOI： 10.1111/cas.14346

Web of Science

PubMed

The Role of Meflin Expression in Fibroblasts During Development of Pulmonary Fibrosis

Hashimoto, N; Nakahara, Y; Sakamoto, K; Enomoto, A; Yokoi, T; Suzuki, A; Inoue, M; Wakahara, K; Hasegawa, Y

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Vol. 201 2020

Meflin-positive cancer-associated fibroblasts inhibit pancreatic carcinogenesis

Mizutani, Y; Kobayashi, H; Enomoto, A; Takahashi, M

CANCER RESEARCH Vol. 79 ( 24 ) 2019.12

Protein Kinase N Promotes Stress-Induced Cardiac Dysfunction Through Phosphorylation of Myocardin-Related Transcription Factor A and Disruption of Its Interaction With Actin. Reviewed International journal

Teruhiro Sakaguchi, Mikito Takefuji, Nina Wettschureck, Tomonari Hamaguchi, Mutsuki Amano, Katsuhiro Kato, Takuma Tsuda, Shunsuke Eguchi, Sohta Ishihama, Yu Mori, Yoshimitsu Yura, Tatsuya Yoshida, Kazumasa Unno, Takahiro Okumura, Hideki Ishii, Yuuki Shimizu, Yasuko K Bando, Koji Ohashi, Noriyuki Ouchi, Atsushi Enomoto, Stefan Offermanns, Kozo Kaibuchi, Toyoaki Murohara

Circulation Vol. 140 ( 21 ) page： 1737 - 1752 2019.11

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

BACKGROUND: Heart failure is a complex syndrome that results from structural or functional impairment of ventricular filling or blood ejection. Protein phosphorylation is a major and essential intracellular mechanism that mediates various cellular processes in cardiomyocytes in response to extracellular and intracellular signals. The RHOA-associated protein kinase (ROCK/Rho-kinase), an effector regulated by the small GTPase RHOA, causes pathological phosphorylation of proteins, resulting in cardiovascular diseases. RHOA also activates protein kinase N (PKN); however, the role of PKN in cardiovascular diseases remains unclear. METHODS: To explore the role of PKNs in heart failure, we generated tamoxifen-inducible, cardiomyocyte-specific PKN1- and PKN2-knockout mice by intercrossing the αMHC-CreERT2 line with Pkn1flox/flox and Pkn2flox/flox mice and applied a mouse model of transverse aortic constriction- and angiotensin II-induced heart failure. To identify a novel substrate of PKNs, we incubated GST-tagged myocardin-related transcription factor A (MRTFA) with recombinant GST-PKN-catalytic domain or GST-ROCK-catalytic domain in the presence of radiolabeled ATP and detected radioactive GST-MRTFA as phosphorylated MRTFA. RESULTS: We demonstrated that RHOA activates 2 members of the PKN family of proteins, PKN1 and PKN2, in cardiomyocytes of mice with cardiac dysfunction. Cardiomyocyte-specific deletion of the genes encoding Pkn1 and Pkn2 (cmc-PKN1/2 DKO) did not affect basal heart function but protected mice from pressure overload- and angiotensin II-induced cardiac dysfunction. Furthermore, we identified MRTFA as a novel substrate of PKN1 and PKN2 and found that MRTFA phosphorylation by PKN was considerably more effective than that by ROCK in vitro. We confirmed that endogenous MRTFA phosphorylation in the heart was induced by pressure overload- and angiotensin II-induced cardiac dysfunction in wild-type mice, whereas cmc-PKN1/2 DKO mice suppressed transverse aortic constriction- and angiotensin II-induced phosphorylation of MRTFA. Although RHOA-mediated actin polymerization accelerated MRTFA-induced gene transcription, PKN1 and PKN2 inhibited the interaction of MRTFA with globular actin by phosphorylating MRTFA, causing increased serum response factor-mediated expression of cardiac hypertrophy- and fibrosis-associated genes. CONCLUSIONS: Our results indicate that PKN1 and PKN2 activation causes cardiac dysfunction and is involved in the transition to heart failure, thus providing unique targets for therapeutic intervention for heart failure.

DOI： 10.1161/CIRCULATIONAHA.119.041019

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PubMed

Meflin-Positive Cancer-Associated Fibroblasts Inhibit Pancreatic Carcinogenesis. Reviewed International journal

Yasuyuki Mizutani, Hiroki Kobayashi, Tadashi Iida, Naoya Asai, Atsushi Masamune, Akitoshi Hara, Nobutoshi Esaki, Kaori Ushida, Shinji Mii, Yukihiro Shiraki, Kenju Ando, Liang Weng, Seiichiro Ishihara, Suzanne M Ponik, Matthew W Conklin, Hisashi Haga, Arata Nagasaka, Takaki Miyata, Makoto Matsuyama, Tomoe Kobayashi, Tsutomu Fujii, Suguru Yamada, Junpei Yamaguchi, Tongtong Wang, Susan L Woods, Daniel Worthley, Teppei Shimamura, Mitsuhiro Fujishiro, Yoshiki Hirooka, Atsushi Enomoto, Masahide Takahashi

Cancer research Vol. 79 ( 20 ) page： 5367 - 5381 2019.10

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

Cancer-associated fibroblasts (CAF) constitute a major component of the tumor microenvironment. Recent observations in genetically engineered mouse models and clinical studies have suggested that there may exist at least two functionally different populations of CAFs, that is, cancer-promoting CAFs (pCAF) and cancer-restraining CAFs (rCAF). Although various pCAF markers have been identified, the identity of rCAFs remains unknown because of the lack of rCAF-specific marker(s). In this study, we found that Meflin, a glycosylphosphatidylinositol-anchored protein that is a marker of mesenchymal stromal/stem cells and maintains their undifferentiated state, is expressed by pancreatic stellate cells that are a source of CAFs in pancreatic ductal adenocarcinoma (PDAC). In situ hybridization analysis of 71 human PDAC tissues revealed that the infiltration of Meflin-positive CAFs correlated with favorable patient outcome. Consistent herewith, Meflin deficiency led to significant tumor progression with poorly differentiated histology in a PDAC mouse model. Similarly, genetic ablation of Meflin-positive CAFs resulted in poor differentiation of tumors in a syngeneic transplantation model. Conversely, delivery of a Meflin-expressing lentivirus into the tumor stroma or overexpression of Meflin in CAFs suppressed the growth of xenograft tumors. Lineage tracing revealed that Meflin-positive cells gave rise to α-smooth muscle actin-positive CAFs that are positive or negative for Meflin, suggesting a mechanism for generating CAF heterogeneity. Meflin deficiency or low expression resulted in straightened stromal collagen fibers, which represent a signature for aggressive tumors, in mouse or human PDAC tissues, respectively. Together, the data suggest that Meflin is a marker of rCAFs that suppress PDAC progression. SIGNIFICANCE: Meflin marks and functionally contributes to a subset of cancer-associated fibroblasts that exert antitumoral effects.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5367/F1.large.jpg.

DOI： 10.1158/0008-5472.CAN-19-0454

Web of Science

PubMed

The new-defined mesenchymal stromal/stem cell marker has a protective role in the development of acute lung injury

Nakahara, Y; Hashimoto, N; Sakamoto, K; Ando, A; Inoue, M; Suzuki, A; Enomoto, A; Hasegawa, Y

EUROPEAN RESPIRATORY JOURNAL Vol. 54 2019.9

TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets. Reviewed International journal

Kunihiko Araki, Amane Araki, Daiyu Honda, Takako Izumoto, Atsushi Hashizume, Yasuhiro Hijikata, Shinichiro Yamada, Yohei Iguchi, Akitoshi Hara, Kazuhiro Ikumi, Kaori Kawai, Shinsuke Ishigaki, Yoko Nakamichi, Shin Tsunekawa, Yusuke Seino, Akiko Yamamoto, Yasunori Takayama, Shihomi Hidaka, Makoto Tominaga, Mica Ohara-Imaizumi, Atsushi Suzuki, Hiroshi Ishiguro, Atsushi Enomoto, Mari Yoshida, Hiroshi Arima, Shin-Ichi Muramatsu, Gen Sobue, Masahisa Katsuno

The Journal of clinical investigation Vol. 129 ( 9 ) page： 3578 - 3593 2019.9

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

TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting both upper and lower motor neurons. Besides motor symptoms, patients with ALS often develop nonneuronal signs including glucose intolerance, but the underlying pathomechanism is still controversial, i.e., whether it is impaired insulin secretion and/or insulin resistance. Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in the islets of autopsied ALS pancreas. Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6) and β cell-specific Tardbp knockout mice. Overexpression of CaV1.2 restored early-phase insulin secretion in Tardbp knocked-down MIN6 cells. Our findings suggest that TDP-43 regulates cellular exocytosis mediated by L-type voltage-dependent calcium channels and thus plays an important role in the early phase of insulin secretion by pancreatic islets. Thus, nuclear loss of TDP-43 is implicated in not only the selective loss of motor neurons but also in glucose intolerance due to impaired insulin secretion at an early stage of ALS.

DOI： 10.1172/JCI124481

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PubMed

Roles of the Mesenchymal Stromal/Stem Cell Marker Meflin in Cardiac Tissue Repair and the Development of Diastolic Dysfunction. Reviewed International journal

Akitoshi Hara, Hiroki Kobayashi, Naoya Asai, Shigeyoshi Saito, Takahiro Higuchi, Katsuhiro Kato, Takahiro Okumura, Yasuko K Bando, Mikito Takefuji, Yasuyuki Mizutani, Yuki Miyai, Shoji Saito, Shoichi Maruyama, Keiko Maeda, Noriyuki Ouchi, Arata Nagasaka, Takaki Miyata, Shinji Mii, Noriyuki Kioka, Daniel L Worthley, Toyoaki Murohara, Masahide Takahashi, Atsushi Enomoto

Circulation research Vol. 125 ( 4 ) page： 414 - 430 2019.8

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

RATIONALE: Myofibroblasts have roles in tissue repair following damage associated with ischemia, aging, and inflammation and also promote fibrosis and tissue stiffening, causing organ dysfunction. One source of myofibroblasts is mesenchymal stromal/stem cells that exist as resident fibroblasts in multiple tissues. We previously identified meflin (mesenchymal stromal cell- and fibroblast-expressing Linx paralogue), a glycosylphosphatidylinositol-anchored membrane protein, as a specific marker of mesenchymal stromal/stem cells and a regulator of their undifferentiated state. The roles of meflin in the development of heart disease, however, have not been investigated. OBJECTIVE: We examined the expression of meflin in the heart and its involvement in cardiac repair after ischemia, fibrosis, and the development of heart failure. METHODS AND RESULTS: We found that meflin has an inhibitory role in myofibroblast differentiation of cultured mesenchymal stromal/stem cells. Meflin expression was downregulated by stimulation with TGF (transforming growth factor)-β, substrate stiffness, hypoxia, and aging. Histological analysis revealed that meflin-positive fibroblastic cells and their lineage cells proliferated in the hearts after acute myocardial infarction and pressure-overload heart failure mouse models. Analysis of meflin knockout mice revealed that meflin is essential for the increase in the number of cells that highly express type I collagen in the heart walls after myocardial infarction induction. When subjected to pressure overload by transverse aortic constriction, meflin knockout mice developed marked cardiac interstitial fibrosis with defective compensation mechanisms. Analysis with atomic force microscopy and hemodynamic catheterization revealed that meflin knockout mice developed stiff failing hearts with diastolic dysfunction. Mechanistically, we found that meflin interacts with bone morphogenetic protein 7, an antifibrotic cytokine that counteracts the action of TGF-β and augments its intracellular signaling. CONCLUSIONS: These data suggested that meflin is involved in cardiac tissue repair after injury and has an inhibitory role in myofibroblast differentiation of cardiac fibroblastic cells and the development of cardiac fibrosis.

DOI： 10.1161/CIRCRESAHA.119.314806

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PubMed

The intercellular expression of type-XVII collagen, laminin-332, and integrin-β1 promote contact following during the collective invasion of a cancer cell population. Reviewed International journal

Kumagai Y, Nio-Kobayashi J, Ishida-Ishihara S, Tachibana H, Omori R, Enomoto A, Ishihara S, Haga H

Biochemical and biophysical research communications Vol. 514 ( 4 ) page： 1115 - 1121 2019.7

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

Cancer cells can invade as a population in various cancer tissues. This phenomenon is called collective invasion, which is associated with the metastatic potential and prognosis of cancer patients. The collectiveness of cancer cells is necessary for collective invasion. However, the mechanism underlying the generation of collectiveness by cancer cells is not well known. In this study, the phenomenon of contact following, where neighboring cells move in the same direction via intercellular adhesion, was investigated. An experimental system was created to observe the two-dimensional invasion using a collagen gel overlay to study contact following in collective invasion. The role of integrin-β1, one of the major extracellular matrix (ECM) receptors, in contact following was examined through the experimental system. Integrin-β1 was localized to the intercellular site in squamous carcinoma cells. Moreover, the intercellular adhesion and contact following were suppressed by treatment of an integrin-β1 inhibitory antibody. ECM proteins such as laminin-332 and type-XVII collagen were also localized to the intercellular site and critical for contact following. Collectively, it was demonstrated that the activity of integrin-β1 and expression of ECM proteins in the intercellular site promote contact following in the collective invasion of a cancer cell population.

DOI： 10.1016/j.bbrc.2019.05.058

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PubMed

Identification of cancer-associated fibroblasts that suppress pancreatic cancer progression

Enomoto, A; Mizutani, Y; Kobayashi, H; Iida, T; Woods, SL; Worthley, DL; Takahashi, M

CANCER RESEARCH Vol. 79 ( 13 ) 2019.7

Dephosphorylation of Girdin by PP2A inhibits breast cancer metastasis. Reviewed

Li J, Enomoto A, Weng L, Sun L, Takahashi M

Biochemical and biophysical research communications Vol. 513 ( 1 ) page： 28 - 34 2019.5

Cancer-associated fibroblasts in gastrointestinal cancer. Reviewed

Kobayashi H, Enomoto A, Woods SL, Burt AD, Takahashi M, Worthley DL

Nature reviews. Gastroenterology & hepatology Vol. 16 ( 5 ) page： 282 - 295 2019.5

CD109: a multifunctional GPI-anchored protein with key roles in tumor progression and physiological homeostasis. Reviewed International journal

Shinji Mii, Atsushi Enomoto, Yukihiro Shiraki, Tetsuro Taki, Yoshiki Murakumo, Masahide Takahashi

Pathology international Vol. 69 ( 5 ) page： 249 - 259 2019.5

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

CD109 is a glycosylphosphatidylinositol-anchored glycoprotein and a member of the α2 -macroglobulin/C3,C4,C5 family of thioester-containing proteins first identified as being expressed on blood cells, including activated T cells and platelets, and a subset of CD34 + bone marrow cells containing megakaryocyte progenitors. Although CD109 carries the biallelic platelet-specific alloantigen Gov, the physiological functions or roles of CD109 in human disease remain largely unknown. It was recently demonstrated that CD109 is expressed in many malignant tumors, including various squamous cell carcinomas and adenocarcinomas, and plays a role as a multifunctional coreceptor. CD109 reportedly associates with transforming growth factor (TGF)-β receptors and negatively regulates TGF-β signaling in keratinocytes. Additionally, CD109 is potentially related to signal transducer and activator of transcription-3 signaling and aberrant cell proliferation. In this review, we describe recent evidence of CD109-specific significance in malignant tumors shown in mouse models and human tissues. Furthermore, we discuss the physiological functions of CD109 in vitro and in vivo, including results of phenotype analyses of CD109-deficient mice exhibiting epidermal hyperplasia and osteopenia.

DOI： 10.1111/pin.12798

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PubMed

Aberrant Active cis-Regulatory Elements Associated with Downregulation of RET Finger Protein Overcome Chemoresistance in Glioblastoma. Reviewed International journal

Ranjit M, Hirano M, Aoki K, Okuno Y, Ohka F, Yamamichi A, Kato A, Maeda S, Motomura K, Matsuo K, Enomoto A, Ino Y, Todo T, Takahashi M, Wakabayashi T, Kato T, Natsume A

Cell reports Vol. 26 ( 9 ) page： 2274 - + 2019.2

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

RET finger protein (RFP) forms a complex with histone deacetylase 1, resulting in aberrant deacetylation of H3K27ac and dysregulation of cis-regulatory elements. We evaluated the modulatory effects of RFP knockdown on cis-regulatory elements, gene expression, and chemosensitivity to temozolomide both in glioblastoma cells and in an intracranial glioblastoma model. The combination of RFP knockdown and temozolomide treatment markedly suppressed the glioblastoma cell growth due to oxidative stress and aberrant cell cycle and increased survival time in mice with glioblastoma. ChIP-seq and RNA-seq revealed that RFP knockdown increased or decreased activity of numerous cis-regulatory elements that lie adjacent to genes that control functions such as apoptosis, mitosis, DNA replication, and cell cycle: FOXO1, TBP2, and PARPBP. This study suggests that RFP contributes to chemoresistance via aberrant deacetylation of histone H3 at K27, whereas dysregulation of RFP-associated cis-regulatory elements in glioma and RFP knockdown combined with temozolomide is an effective treatment strategy for lethal glioma.

DOI： 10.1016/j.celrep.2019.01.109

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PubMed

Aberrant Active cis-Regulatory Elements Associated with Downregulation of RET Finger Protein Overcome Chemoresistance in Glioblastoma Reviewed

Ranjit M, Hirano M, Aoki K, Okuno Y, Ohka F, Yamamichi A, Kato A, Maeda S, Motomura K, Matsuo K, Enomoto A, Ino Y, Todo T, Takahashi M, Wakabayashi T, Kato T, Natsume A.

Cell Rep Vol. 26 ( 9 ) page： 2274-2281.e5. 2019.2

Cancer-associated fibroblasts in gastrointestinal cancer Reviewed

Kobayashi H, Enomoto A, Woods SL, Burt AD, Takahashi M, Worthley DL.

Nat Rev Gastroenterol Hepatol. 2019.2

A rare pseudo tumour in the extraembryonic coelom in first trimester of pregnancy: ultrasound and pathology. Reviewed International journal

Sumigama S, Enomoto A, Matsukawa S, Ushida T, Imai K, Nakano T, Kotani T, Kikkawa F

Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology Vol. 39 ( 4 ) page： 545 - 546 2019

Force-dependent arrest of keratinocyte proliferation and its potential defect in skin cancer.

Hirata, H; Enomoto, A; Sunagawa, M; Dobrokhotov, O; Takahashi, M; Samsonov, M; Sokabe, M

MOLECULAR BIOLOGY OF THE CELL Vol. 29 ( 26 ) 2018.12

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Papers - ENOMOTO, Atsushi