Updated on 2022/05/12

写真a

 
SHIRAKI Yukihiro
 
Organization
Graduate School of Medicine Center for Neural Disease and Cancer Division Assistant Professor
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine Department of Medicine
Title
Assistant Professor
External link

Degree 1

  1. 博士(医学) ( 2017.12   名古屋大学 ) 

Research Areas 1

  1. Life Science / Experimental pathology

Research History 2

  1. Nagoya University Graduate School of Medicine   Division for Medical Research Engineering   Assistant Professor

    2017.6

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    Country:Japan

  2. Nagoya University Graduate School of Medicine   Division for Medical Research Engineering   Designated assistant professor

    2017.4 - 2017.5

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    Country:Japan

Education 2

  1. Nagoya University   Graduate School, Division of Medical Sciences

    2013.4 - 2017.3

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    Country: Japan

  2. Nagoya University   Faculty of Medicine

    - 2008.3

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    Country: Japan

Professional Memberships 2

  1. 日本病理学会

  2. 日本癌学会

 

Papers 25

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

    Iida T, Mizutani Y, Esaki N, Ponik SM, Burkel BM, Weng L, Kuwata K, Masamune A, Ishihara S, Haga H, Kataoka K, Mii S, Shiraki Y, Ishikawa T, Ohno E, Kawashima H, Hirooka Y, Fujishiro M, Takahashi M, Enomoto A

    Oncogene     2022.5

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

    DOI: 10.1038/s41388-022-02336-4

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

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

    ONCOGENE   Vol. 41 ( 19 ) page: 2764 - 2777   2022.4

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Oncogene  

    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

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  3. A novel renal perivascular mesenchymal cell subset gives rise to fibroblasts distinct from classic myofibroblasts

    Minatoguchi Shun, Saito Shoji, Furuhashi Kazuhiro, Sawa Yuriko, Okazaki Masaki, Shimamura Yuko, Kaihan Ahmad Baseer, Hashimoto Yusaku, Yasuda Yoshinari, Hara Akitoshi, Mizutani Yasuyuki, Ando Ryota, Kato Noritoshi, Ishimoto Takuji, Tsuboi Naotake, Esaki Nobutoshi, Matsuyama Makoto, Shiraki Yukihiro, Kobayashi Hiroki, Asai Naoya, Enomoto Atsushi, Maruyama Shoichi

    SCIENTIFIC REPORTS   Vol. 12 ( 1 ) page: 5389   2022.3

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Scientific Reports  

    Perivascular mesenchymal cells (PMCs), which include pericytes, give rise to myofibroblasts that contribute to chronic kidney disease progression. Several PMC markers have been identified; however, PMC heterogeneity and functions are not fully understood. Here, we describe a novel subset of renal PMCs that express Meflin, a glycosylphosphatidylinositol-anchored protein that was recently identified as a marker of fibroblasts essential for cardiac tissue repair. Tracing the lineage of Meflin+ PMCs, which are found in perivascular and periglomerular areas and exhibit renin-producing potential, showed that they detach from the vasculature and proliferate under disease conditions. Although the contribution of Meflin+ PMCs to conventional α-SMA+ myofibroblasts is low, they give rise to fibroblasts with heterogeneous α-SMA expression patterns. Genetic ablation of Meflin+ PMCs in a renal fibrosis mouse model revealed their essential role in collagen production. Consistent with this, human biopsy samples showed that progressive renal diseases exhibit high Meflin expression. Furthermore, Meflin overexpression in kidney fibroblasts promoted bone morphogenetic protein 7 signals and suppressed myofibroblastic differentiation, implicating the roles of Meflin in suppressing tissue fibrosis. These findings demonstrate that Meflin marks a PMC subset that is functionally distinct from classic pericytes and myofibroblasts, highlighting the importance of elucidating PMC heterogeneity.

    DOI: 10.1038/s41598-022-09331-5

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  4. Meflin-positive cancer-associated fibroblasts enhance tumor response to immune checkpoint blockade

    Miyai Yuki, Sugiyama Daisuke, Hase Tetsunari, Asai Naoya, Taki Tetsuro, Nishida Kazuki, Fukui Takayuki, Chen-Yoshikawa Toyofumi Fengshi, Kobayashi Hiroki, Mii Shinji, Shiraki Yukihiro, Hasegawa Yoshinori, Nishikawa Hiroyoshi, Ando Yuichi, Takahashi Masahide, Enomoto Atsushi

    LIFE SCIENCE ALLIANCE   Vol. 5 ( 6 )   2022.3

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Life Science Alliance  

    Cancer-associated fibroblasts (CAFs) are an integral component of the tumor microenvironment (TME). Most CAFs shape the TME toward an immunosuppressive milieu and attenuate the efficacy of immune checkpoint blockade (ICB) therapy. However, the detailed mechanism of how heterogeneous CAFs regulate tumor response to ICB therapy has not been defined. Here, we show that a recently defined CAF subset characterized by the expression of Meflin, a glycosylphosphatidylinositol-anchored protein marker of mesenchymal stromal/stem cells, is associated with survival and favorable therapeutic response to ICB monotherapy in patients with non-small cell lung cancer (NSCLC). The prevalence of Meflin-positive CAFs was positively correlated with CD4-positive T-cell infiltration and vascularization within non-small cell lung cancer tumors. Meflin deficiency and CAF-specific Meflin overexpression resulted in defective and enhanced ICB therapy responses in syngeneic tumors in mice, respectively. These findings suggest the presence of a CAF subset that promotes ICB therapy efficacy, which adds to our understanding of CAF functions and heterogeneity.

    DOI: 10.26508/lsa.202101230

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  5. Matrix remodeling-associated protein 8 is a marker of a subset of cancer-associated fibroblasts in pancreatic cancer

    Ichihara Ryosuke, Shiraki Yukihiro, Mizutani Yasuyuki, Iida Tadashi, Miyai Yuki, Esaki Nobutoshi, Kato Akira, Mii Shinji, Ando Ryota, Hayashi Masamichi, Takami Hideki, Fujii Tsutomu, Takahashi Masahide, Enomoto Atsushi

    PATHOLOGY INTERNATIONAL   Vol. 72 ( 3 ) page: 161 - 175   2022.3

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Pathology International  

    Cancer-associated fibroblasts (CAFs), a compartment of the tumor microenvironment, were previously thought to be a uniform cell population that promotes cancer progression. However, recent studies have shown that CAFs are heterogeneous and that there are at least two types of CAFs, that is, cancer-promoting and -restraining CAFs. We previously identified Meflin as a candidate marker of cancer-restraining CAFs (rCAFs) in pancreatic ductal adenocarcinoma (PDAC). The precise nature of rCAFs, however, has remained elusive owing to a lack of understanding of their comprehensive gene signatures. Here, we screened genes whose expression correlated with Meflin in single-cell transcriptomic analyses of human cancers. Among the identified genes, we identified matrix remodeling-associated protein 8 (MXRA8), which encodes a type I transmembrane protein with unknown molecular function. Analysis of MXRA8 expression in human PDAC samples showed that MXRA8 was differentially co-expressed with other CAF markers. Moreover, in patients with PDAC or syngeneic tumors developed in MXRA8-knockout mice, MXRA8 expression did not affect the roles of CAFs in cancer progression, and the biological importance of MXRA8+ CAFs is still unclear. Overall, we identified MXRA8 as a new CAF marker; further studies are needed to determine the relevance of this marker.

    DOI: 10.1111/pin.13198

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  6. Newly established patient-derived organoid model of intracranial meningioma

    Yamazaki Shintaro, Ohka Fumiharu, Hirano Masaki, Shiraki Yukihiro, Motomura Kazuya, Tanahashi Kuniaki, Tsujiuchi Takashi, Motomura Ayako, Aoki Kosuke, Shinjo Keiko, Murofushi Yoshiteru, Kitano Yotaro, Maeda Sachi, Kato Akira, Shimizu Hiroyuki, Yamaguchi Junya, Adilijiang Alimu, Wakabayashi Toshihiko, Saito Ryuta, Enomoto Atsushi, Kondo Yutaka, Natsume Atsushi

    NEURO-ONCOLOGY   Vol. 23 ( 11 ) page: 1936 - 1948   2021.11

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Neuro-Oncology  

    Background: Recent comprehensive studies have revealed several molecular alterations that are frequently found in meningiomas. However, effective treatment reagents targeting specific molecular alterations have not yet been identified because of the limited number of representative research models of meningiomas. Methods: We performed organoid cultures using meningioma cells and meningioma tumor tissues. Using immunohistochemistry and molecular analyses consisting of whole-exome sequencing, RNA-seq, and DNA methylation analyses, we compared the histological findings and molecular profiling of organoid models with those of parental tumors. Further, using these organoid models together with a public database of meningiomas, we explored molecular alterations, which are a potent treatment target for meningioma. Results: We established 18 organoid models comprising of two malignant meningioma cells (HKBMM and IOMM-Lee), 10 benign meningiomas, four malignant meningiomas, and two solitary fibrous tumors (SFTs). The organoids exhibited consistent histological features and molecular profiles with those of the parental tumors. Using a public database, we identified that upregulated forkhead box M1 (FOXM1) was correlated with increased tumor proliferation. Overexpression of FOXM1 in benign meningioma organoids increased organoid proliferation; depletion of FOXM1 in malignant organoids decreased proliferation. Additionally, thiostrepton, a FOXM1 inhibitor combined with radiation therapy, significantly inhibited the proliferation of malignant meningioma organoid models. Conclusions: An organoid model for meningioma enabled us to elucidate the tumor biology of meningioma along with potent treatment targets for meningioma.

    DOI: 10.1093/neuonc/noab155

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  7. The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis-associated liver tumors in a novel murine model

    Yoshioka Naoki, Tanaka Miyako, Ochi Kozue, Watanabe Akiko, Ono Kenji, Sawada Makoto, Ogi Tomoo, Itoh Michiko, Ito Ayaka, Shiraki Yukihiro, Enomoto Atsushi, Ishigami Masatoshi, Fujishiro Mitsuhiro, Ogawa Yoshihiro, Suganami Takayoshi

    BIOMEDICINE & PHARMACOTHERAPY   Vol. 140   page: 111738   2021.8

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Biomedicine and Pharmacotherapy  

    Background: Diabetes and obesity contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). However, how diabetes and obesity accelerate liver tumorigenesis remains to be fully understood. Moreover, to verify the therapeutic potential of anti-diabetic drugs, there exists a strong need for appropriate animal models that recapitulate human pathophysiology of NASH and HCC. Methods: We established a novel murine model of NASH-associated liver tumors using genetically obese melanocortin 4 receptor-deficient mice fed on Western diet in combination with a chemical procarcinogen, and verified the validity of our model in evaluating drug efficacy. Findings: Our model developed multiple liver tumors together with obesity, diabetes, and NASH within a relatively short period (approximately 3 months). In this model, sodium glucose cotransporter 2 inhibitor Tofogliflozin prevented the development of NASH-like liver phenotypes and the progression of liver tumors. Tofogliflozin attenuated p21 expression of hepatocytes in non-tumorous lesions in the liver. Interpretation: Tofogliflozin treatment attenuates cellular senescence of hepatocytes under obese and diabetic conditions. This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat NASH-associated HCC.

    DOI: 10.1016/j.biopha.2021.111738

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  8. Meflin defines mesenchymal stem cells and/or their early progenitors with multilineage differentiation capacity

    Hara Akitoshi, Kato Katsuhiro, Ishihara Toshikazu, Kobayashi Hiroki, Asai Naoya, Mii Shinji, Shiraki Yukihiro, Miyai Yuki, Ando Ryota, Mizutani Yasuyuki, Iida Tadashi, Takefuji Mikito, Murohara Toyoaki, Takahashi Masahide, Enomoto Atsushi

    GENES TO CELLS   Vol. 26 ( 7 ) page: 495 - 512   2021.7

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Genes to Cells  

    Mesenchymal stem cells (MSCs) are the likely precursors of multiple lines of mesenchymal cells. The existence of bona fide MSCs with self-renewal capacity and differentiation potential into all mesenchymal lineages, however, has been unclear because of the lack of MSC-specific marker(s) that are not expressed by the terminally differentiated progeny. Meflin, a glycosylphosphatidylinositol-anchored protein, is an MSC marker candidate that is specifically expressed in rare stromal cells in all tissues. Our previous report showed that Meflin expression becomes down-regulated in bone marrow-derived MSCs cultured on plastic, making it difficult to examine the self-renewal and differentiation of Meflin-positive cells at the single-cell level. Here, we traced the lineage of Meflin-positive cells in postnatal and adult mice, showing that those cells differentiated into white and brown adipocytes, osteocytes, chondrocytes and skeletal myocytes. Interestingly, cells derived from Meflin-positive cells formed clusters of differentiated cells, implying the in situ proliferation of Meflin-positive cells or their lineage-committed progenitors. These results, taken together with previous findings that Meflin expression in cultured MSCs was lost upon their multilineage differentiation, suggest that Meflin is a useful potential marker to localize MSCs and/or their immature progenitors in multiple tissues.

    DOI: 10.1111/gtc.12855

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  9. Size and surface modification of silica nanoparticles affect the severity of lung toxicity by modulating endosomal ROS generation in macrophages

    Inoue Masahide, Sakamoto Koji, Suzuki Atsushi, Nakai Shinya, Ando Akira, Shiraki Yukihiko, Nakahara Yoshio, Omura Mika, Enomoto Atsushi, Nakase Ikuhiko, Sawada Makoto, Hashimoto Naozumi

    PARTICLE AND FIBRE TOXICOLOGY   Vol. 18 ( 1 )   2021.6

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Particle and Fibre Toxicology  

    Background: As the application of silica nanomaterials continues to expand, increasing chances of its exposure to the human body and potential harm are anticipated. Although the toxicity of silica nanomaterials is assumed to be affected by their physio-chemical properties, including size and surface functionalization, its molecular mechanisms remain unclear. We hypothesized that analysis of intracellular localization of the particles and subsequent intracellular signaling could reveal a novel determinant of inflammatory response against silica particles with different physico-chemical properties. Results: We employed a murine intratracheal instillation model of amorphous silica nanoparticles (NPs) exposure to compare their in vivo toxicities in the respiratory system. Pristine silica-NPs of 50 nm diameters (50 nm-plain) induced airway-centered lung injury with marked neutrophilic infiltration. By contrast, instillation of pristine silica particles of a larger diameter (3 μm; 3 μm-plain) significantly reduced the severity of lung injury and neutrophilic infiltration, possibly through attenuated induction of neutrophil chemotactic chemokines including MIP2. Ex vivo analysis of alveolar macrophages as well as in vitro assessment using RAW264.7 cells revealed a remarkably lower cellular uptake of 3 μm-plain particles compared with 50 nm-plain, which is assumed to be the underlying mechanism of attenuated immune response. The severity of lung injury and neutrophilic infiltration was also significantly reduced after intratracheal instillation of silica NPs with an amine surface modification (50 nm-NH2) when compared with 50 nm-plain. Despite unchanged efficacy in cellular uptake, treatment with 50 nm-NH2 induced a significantly attenuated immune response in RAW264.7 cells. Assessment of intracellular redox signaling revealed increased reactive oxygen species (ROS) in endosomal compartments of RAW264.7 cells treated with 50 nm-plain when compared with vehicle-treated control. In contrast, augmentation of endosomal ROS signals in cells treated with 50 nm-NH2 was significantly lower. Moreover, selective inhibition of NADPH oxidase 2 (NOX2) was sufficient to inhibit endosomal ROS bursts and induction of chemokine expressions in cells treated with silica NPs, suggesting the central role of endosomal ROS generated by NOX2 in the regulation of the inflammatory response in macrophages that endocytosed silica NPs. Conclusions: Our murine model suggested that the pulmonary toxicity of silica NPs depended on their physico-chemical properties through distinct mechanisms. Cellular uptake of larger particles by macrophages decreased, while surface amine modification modulated endosomal ROS signaling via NOX2, both of which are assumed to be involved in mitigating immune response in macrophages and resulting lung injury.

    DOI: 10.1186/s12989-021-00415-0

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  10. Urinary MicroRNA-Based Diagnostic Model for Central Nervous System Tumors Using Nanowire Scaffolds

    Kitano Yotaro, Aoki Kosuke, Ohka Fumiharu, Yamazaki Shintaro, Motomura Kazuya, Tanahashi Kuniaki, Hirano Masaki, Naganawa Tsuyoshi, Iida Mikiko, Shiraki Yukihiro, Nishikawa Tomohide, Shimizu Hiroyuki, Yamaguchi Junya, Maeda Sachi, Suzuki Hidenori, Wakabayashi Toshihiko, Baba Yoshinobu, Yasui Takao, Natsume Atsushi

    ACS APPLIED MATERIALS & INTERFACES   Vol. 13 ( 15 ) page: 17316 - 17329   2021.4

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:ACS Applied Materials and Interfaces  

    There are no accurate mass screening methods for early detection of central nervous system (CNS) tumors. Recently, liquid biopsy has received a lot of attention for less-invasive cancer screening. Unlike other cancers, CNS tumors require efforts to find biomarkers due to the blood-brain barrier, which restricts molecular exchange between the parenchyma and blood. Additionally, because a satisfactory way to collect urinary biomarkers is lacking, urine-based liquid biopsy has not been fully investigated despite the fact that it has some advantages compared to blood or cerebrospinal fluid-based biopsy. Here, we have developed a mass-producible and sterilizable nanowire-based device that can extract urinary microRNAs efficiently. Urinary microRNAs from patients with CNS tumors (n = 119) and noncancer individuals (n = 100) were analyzed using a microarray to yield comprehensive microRNA expression profiles. To clarify the origin of urinary microRNAs of patients with CNS tumors, glioblastoma organoids were generated. Glioblastoma organoid-derived differentially expressed microRNAs (DEMs) included 73.4% of the DEMs in urine of patients with parental tumors but included only 3.9% of those in urine of noncancer individuals, which suggested that many CNS tumor-derived microRNAs could be identified in urine directly. We constructed the diagnostic model based on the expression of the selected microRNAs and found that it was able to differentiate patients and noncancer individuals at a sensitivity and specificity of 100 and 97%, respectively, in an independent dataset. Our findings demonstrate that urinary microRNAs extracted with the nanowire device offer a well-fitted strategy for mass screening of CNS tumors.

    DOI: 10.1021/acsami.1c01754

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  11. The Balance of Stromal BMP Signaling Mediated by GREM1 and ISLR Drives Colorectal Carcinogenesis

    Kobayashi Hiroki, Gieniec Krystyna A., Wright Josephine A., Wang Tongtong, Asai Naoya, Mizutani Yasuyuki, Lida Tadashi, Ando Ryota, Suzuki Nobumi, Lannagan Tamsin R. M., Ng Jia Q., Hara Akitoshi, Shiraki Yukihiro, Mii Shinji, Ichinose Mari, Vrbanac Laura, Lawrence Matthew J., Sammour Tarik, Uehara Kay, Davies Gareth, Lisowski Leszek, Alexander Ian E., Hayakawa Yoku, Butler Lisa M., Zannettino Andrew C. W., Din M. Omar, Hasty Jeff, Burt Alastair D., Leedham Simon J., Rustgi Anil K., Mukherjee Siddhartha, Wang Timothy C., Enomoto Atsushi, Takahashi Masahide, Worthley Daniel L., Woods Susan L.

    GASTROENTEROLOGY   Vol. 160 ( 4 ) page: 1224 - +   2021.3

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Gastroenterology  

    Background & Aims: Cancer-associated fibroblasts (CAFs), key constituents of the tumor microenvironment, either promote or restrain tumor growth. Attempts to therapeutically target CAFs have been hampered by our incomplete understanding of these functionally heterogeneous cells. Key growth factors in the intestinal epithelial niche, bone morphogenetic proteins (BMPs), also play a critical role in colorectal cancer (CRC) progression. However, the crucial proteins regulating stromal BMP balance and the potential application of BMP signaling to manage CRC remain largely unexplored. Methods: Using human CRC RNA expression data, we identified CAF-specific factors involved in BMP signaling, then verified and characterized their expression in the CRC stroma by in situ hybridization. CRC tumoroids and a mouse model of CRC hepatic metastasis were used to test approaches to modify BMP signaling and treat CRC. Results: We identified Grem1 and Islr as CAF-specific genes involved in BMP signaling. Functionally, GREM1 and ISLR acted to inhibit and promote BMP signaling, respectively. Grem1 and Islr marked distinct fibroblast subpopulations and were differentially regulated by transforming growth factor β and FOXL1, providing an underlying mechanism to explain fibroblast biological dichotomy. In patients with CRC, high GREM1 and ISLR expression levels were associated with poor and favorable survival, respectively. A GREM1-neutralizing antibody or fibroblast Islr overexpression reduced CRC tumoroid growth and promoted Lgr5+ intestinal stem cell differentiation. Finally, adeno-associated virus 8 (AAV8)–mediated delivery of Islr to hepatocytes increased BMP signaling and improved survival in our mouse model of hepatic metastasis. Conclusions: Stromal BMP signaling predicts and modifies CRC progression and survival, and it can be therapeutically targeted by novel AAV-directed gene delivery to the liver.

    DOI: 10.1053/j.gastro.2020.11.011

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  12. CD109 regulates in vivo tumor invasion in lung adenocarcinoma through TGF-beta signaling

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

    CANCER SCIENCE   Vol. 112   page: 815 - 815   2021.2

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  13. CD109 regulates in vivo tumor invasion in lung adenocarcinoma through TGF-beta signaling

    Taki Tetsuro, Shiraki Yukihiro, Enomoto Atsushi, Weng Liang, Chen Chen, Asai Naoya, Murakumo Yoshiki, Yokoi Kohei, Takahashi Masahide, Mii Shinji

    CANCER SCIENCE   Vol. 111 ( 12 ) page: 4616 - 4628   2020.12

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Cancer Science  

    Stromal invasion is considered an important prognostic factor in patients with lung adenocarcinoma. The mechanisms underlying the formation of tumor stroma and stromal invasion have been studied in the lung; however, they are still unclear. CD109 is a glycosylphosphatidylinositol-anchored glycoprotein highly expressed in several types of human malignant tumors including lung cancers. In this study, we investigated the in vivo functions of CD109 protein in malignant lung tumors. Initially, we identified an association between higher expression of CD109 protein in human lung adenocarcinoma and a significantly worse prognosis, according to immunohistochemical analysis. We also showed that CD109 deficiency significantly reduced the area of stromal invasive lesions in a genetically engineered CD109-deficient lung adenocarcinoma mouse model, which correlated with the results observed in human lung adenocarcinoma. Furthermore, we identified latent TGF-β binding protein-1 (LTBP1) as a CD109-interacting protein using mass spectrometry and confirmed their interaction by co-immunoprecipitation. Importantly, increased CD109 expression enhanced stromal TGF-β activation in the presence of LTBP1. Therefore, these data suggest the significance of the regulation of TGF-β signaling through CD109 and LTBP1 interaction in tumor stroma and also reveal the importance of CD109 expression levels in promoting lung cancer cell proliferation, migration, and invasion, and thus predicting the outcome of patients suffering from lung adenocarcinoma. Therefore, CD109 protein could be a potential therapeutic target for this disease.

    DOI: 10.1111/cas.14673

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  14. The Daple-CK1 epsilon complex regulates Dvl2 phosphorylation and canonical Wnt signaling

    Esaki Nobutoshi, Enomoto Atsushi, Takagishi Maki, Mizutani Yasuyuki, Iida Tadashi, Ushida Kaori, Shiraki Yukihiro, Mii Shinji, Takahashi Masahide

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   Vol. 532 ( 3 ) page: 406 - 413   2020.11

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Biochemical and Biophysical Research Communications  

    The canonical Wnt signaling pathway plays a crucial role in embryonic development, tissue homeostasis and cancer progression. The binding of Wnt ligands to their cognate receptors, the Frizzled (Fzd) family of proteins, recruits Dishevelled segment polarity protein (Dvl) to the plasma membrane and induces its phosphorylation via casein kinase 1 (CK1), which leads to the activation of β-catenin. Previous studies showed that Dishevelled-associating protein with a high frequency of leucine residues (Daple) is an important component of the Wnt signaling pathway and essential for Dvl phosphorylation. However, the mechanism by which Daple promotes CK1-mediated phosphorylation of Dvl is not fully understood. In this study, we found that Daple overexpression induced CK1ε-mediated Dvl2 phosphorylation at threonine 224 (Thr224). A Daple mutant (Daple ΔGCV) that lacks a carboxyl-terminal motif to associate with Dvl, retained the ability to interact with CK1ε, but did not induce Dvl phosphorylation, suggesting the importance of the Daple/Dvl/CK1ε trimeric protein complex. We further found that Thr224 phosphorylation of Dvl was required for full activation of β-catenin transcriptional activity. Consistent with this, wild-type Daple promoted β-catenin transcriptional activity, following dissociation of β-catenin and axin. Finally, Wnt3a stimulation increased the membrane localization of Daple and its association with Dvl, and Daple knockdown attenuated Wnt3a-mediated β-catenin transcriptional activity. Collectively, these data suggested a essential role of spatial Daple localization in CK1ε-mediated activation of Dvl in the canonical Wnt signaling pathway.

    DOI: 10.1016/j.bbrc.2020.08.066

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  15. Complex roles of the actin-binding protein Girdin/GIV in DNA damage-induced apoptosis of cancer cells

    Chen Chen, Enomoto Atsushi, Weng Liang, Taki Tetsuro, Shiraki Yukihiro, Mii Shinji, Ichihara Ryosuke, Kanda Mitsuro, Koike Masahiko, Kodera Yasuhiro, Takahashi Masahide

    CANCER SCIENCE   Vol. 111 ( 11 ) page: 4303 - 4317   2020.11

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Cancer Science  

    The actin-binding protein Girdin is a hub protein that interacts with multiple proteins to regulate motility and Akt and trimeric G protein signaling in cancer cells. Girdin expression correlates with poor outcomes in multiple human cancers. However, those findings are not universal, as they depend on study conditions. Those data suggest that multiple aspects of Girdin function and its role in tumor cell responses to anticancer therapeutics must be reconsidered. In the present study, we found that Girdin is involved in DNA damage-induced cancer cell apoptosis. An esophageal cancer cell line that exhibited high Girdin expression showed a marked sensitivity to UV-mediated DNA damage compared to a line with low Girdin expression. When transcriptional activation of endogenous Girdin was mediated by an engineered CRISPR/Cas9 activation system, sensitivity to DNA damage increased in both stationary and migrating HeLa cancer cells. High Girdin expression was associated with dysregulated cell cycle progression and prolonged G1 and M phases. These features were accompanied by p53 activation, which conceivably increases cancer cell vulnerability to UV exposure. These data highlight the importance of understanding complex Girdin functions that influence cancer cell sensitivity to therapeutics.

    DOI: 10.1111/cas.14637

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  16. Stromal imbalance of bone morphogenetic protein signaling drives colorectal carcinogenesis

    Kobayashi H., Gieniec K., Wright J., Wang T., Asai N., Mizutani Y., Ida T., Ando R., Suzuki N., Lannagan T., Ng J., Hara A., Shiraki Y., Mii S., Ichinose M., Vrbanac L., Lawrence M., Sammour T., Uehara K., Davies G., Lisowski L., Alexander I., Hayakawa Y., Butler L., Zannettino A., Din M. O., Hasty J., Burt A., Leedham S., Rustgi A., Mukherjee S., Wang T. C., Enomoto A., Takahashi M., Worthley D., Woods S.

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   Vol. 35   page: 160 - 160   2020.11

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  17. Meflin-Positive Cancer-Associated Fibroblasts Inhibit Pancreatic Carcinogenesis

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

    CANCER RESEARCH   Vol. 79 ( 20 ) page: 5367 - 5381   2019.10

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Cancer Research  

    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 a-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.

    DOI: 10.1158/0008-5472.CAN-19-0454

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

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

    PATHOLOGY INTERNATIONAL   Vol. 69 ( 5 ) page: 249 - 259   2019.5

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Pathology International  

    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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  19. Remarkable Short-Term Regression of a Posterior Mediastinum Metastasis From Primary Intraosseous Carcinoma Treated With Nivolumab: A Case Report.

    Kimura M, Shiraki Y, Ishibashi K, Umemura M

    Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons   Vol. 77 ( 3 ) page: 555.e1 - 555.e6   2019.3

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    DOI: 10.1016/j.joms.2018.11.016

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  20. Dissection of the function of CD109 in lung adenocarcinoma

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

    CANCER SCIENCE   Vol. 109   page: 1407-1407   2018.12

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  21. The role of CD109 in PDGFB-induced glioma mouse model for sensitivity to Temozolomide

    Shiraki Yukihiro, Mii Shinji, Asai Naoya, Enomoto Atsushi, Momota Hiroyuki, Natsume Atsushi, Wakabayashi Toshihiko, Takahashi Masahide

    CANCER SCIENCE   Vol. 109   page: 1130-1130   2018.1

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  22. Significance of perivascular tumour cells defined by CD109 expression in progression of glioma

    Shiraki Yukihiro, Mii Shinji, Enomoto Atsushi, Momota Hiroyuki, Han Yi-Peng, Kato Takuya, Ushida Kaori, Kato Akira, Asai Naoya, Murakumo Yoshiki, Aoki Kosuke, Suzuki Hiromichi, Ohka Fumiharu, Wakabayashi Toshihiko, Todo Tomoki, Ogawa Seishi, Natsume Atsushi, Takahashi Masahide

    JOURNAL OF PATHOLOGY   Vol. 243 ( 4 ) page: 468 - 480   2017.12

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

    DOI: 10.1002/path.4981

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  23. Significance of low mTORC1 activity in defining the characteristics of brain tumor stem cells

    Han Yi-Peng, Enomoto Atsushi, Shiraki Yukihiro, Wang Shen-Qi, Wang Xiaoze, Toyokuni Shinya, Asai Naoya, Ushida Kaori, Ara Hosne, Ohka Fumiharu, Wakabayashi Toshihiko, Ma Jie, Natsume Atsushi, Takahashi Masahide

    NEURO-ONCOLOGY   Vol. 19 ( 5 ) page: 636 - 647   2017.5

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

    DOI: 10.1093/neuonc/now237

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  24. Suppression of skin tumorigenesis in CD109-deficient mice

    Sunagawa Masaki, Mii Shinji, Enomoto Atsushi, Kato Takuya, Murakumo Yoshiki, Shiraki Yukihiro, Asai Naoya, Asai Masato, Nagino Masato, Takahashi Masahide

    ONCOTARGET   Vol. 7 ( 50 ) page: 82836 - 82850   2016.12

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    CD109 is a glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed in several types of human cancers, particularly squamous cell carcinomas. We previously reported that CD109-deficient mice exhibit epidermal hyperplasia and chronic skin inflammation. Although we found that CD109 regulates differentiation of keratinocytes in vivo, the function of CD109 in tumorigenesis remains unknown. In this study, we investigated the role of CD109 in skin tumorigenesis using a twostage carcinogenesis model in CD109-deficient mice with chronic skin inflammation. Immunohistochemical analysis revealed a higher level of TGF-β protein expression in the dermis of CD109-deficient mice than in that of wild-type mice. Additionally, immunofluorescence analysis showed that Smad2 phosphorylation and Nrf2 expression were enhanced in primary keratinocytes from CD109-deficient mice compared with in those from wild-type mice. Although no significant difference was found in conversion rates from papilloma to carcinoma between wild-type and CD109- deficient mice in the carcinogenesis model, we observed fewer and smaller papillomas in CD109-deficient mice than in wild-type mice. Apoptosis and DNA damage marker levels were significantly reduced in CD109-deficient skin compared with in wildtype skin at 24 h after 7, 12-dimethylbenz (α) anthracene treatment. Furthermore, mutation-specific PCR revealed that the mutation frequency of the H-ras gene was less in CD109-deficient skin than in wild-type skin in this model. These results suggest that CD109 deficiency suppresses skin tumorigenesis by enhancing TGF-β/Smad/Nrf2 pathway activity and decreasing the mutation frequency of the H-ras gene.

    DOI: 10.18632/oncotarget.12653

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  25. Stinging in the oral cavity caused by ingestion of the sperm bags of a squid: a case report.

    Shiraki Y, Kawai K, Kojima S, Suzuki Y, Ono K

    Pathology international   Vol. 61 ( 12 ) page: 749 - 51   2011.12

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    DOI: 10.1111/j.1440-1827.2011.02722.x

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KAKENHI (Grants-in-Aid for Scientific Research) 2

  1. 神経変性疾患における疾患抑制性血管周囲線維芽細胞の機能解析と治療への応用

    Grant number:22K15440  2022.4 - 2026.3

    科学研究費助成事業  若手研究

    白木 之浩

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    Authorship:Principal investigator 

    Grant amount:\4550000 ( Direct Cost: \3500000 、 Indirect Cost:\1050000 )

  2. Functional analysis of CD109 in Brain Tumor.

    Grant number:18K15116  2018.4 - 2021.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Early-Career Scientists

    Shiraki Yukihiro

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    Authorship:Principal investigator 

    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    We identified latent TGF-β binding protein-1 (LTBP1) as a CD109-interacting protein using mass spectrometry and confirmed their interaction by co-immunoprecipitation. CD109 expression enhanced TGF-β activation in the presence of LTBP1.
    Although we tried to develop antibody drug against CD109, we could not obtain notarizing antibody or antibody with ADCC activity.