Faculty Profiles - ENOMOTO, Atsushi

Papers - ENOMOTO, Atsushi

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CD109 expression in tumor cells and stroma correlates with progression and prognosis in pancreatic cancer. Reviewed International journal

Kai Adachi, Yasutaka Sakurai, Masaaki Ichinoe, Masayoshi Tadehara, Akihiro Tamaki, Yurika Kesen, Takuya Kato, Shinji Mii, Atsushi Enomoto, Masahide Takahashi, Wasaburo Koizumi, Yoshiki Murakumo

Virchows Archiv : an international journal of pathology Vol. 480 ( 4 ) page： 819 - 829 2022.4

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

CD109 is a glycosylphosphatidylinositol-anchored glycoprotein, whose expression is upregulated in some types of malignant tumors. High levels of CD109 in tumor cells have been reported to correlate with poor prognosis; however, significance of CD109 stromal expression in human malignancy has not been elucidated. In this study, we investigated the tumorigenic properties of CD109 in pancreatic ductal adenocarcinoma (PDAC). Immunohistochemical analysis of 92 PDAC surgical specimens revealed that positive CD109 expression in tumor cells was significantly associated with poor prognosis (disease-free survival, p = 0.003; overall survival, p = 0.002), and was an independent prognostic factor (disease-free survival, p = 0.0173; overall survival, p = 0.0104) in PDAC. Furthermore, CD109 expression was detected in the stroma surrounding tumor cells, similar to that of α-smooth muscle actin, a histological marker of cancer-associated fibroblasts. The stromal CD109 expression significantly correlated with tumor progression in PDAC (TNM stage, p = 0.033; N factor, p = 0.024; lymphatic invasion, p = 0.028). In addition, combined assessment of CD109 in tumor cells and stroma could identify the better prognosis group of patients from the entire patient population. In MIA PaCa-2 PDAC cell line, we demonstrated the involvement of CD109 in tumor cell motility, but not in PANC-1. Taken together, CD109 not only in the tumor cells but also in the stroma is involved in the progression and prognosis of PDAC, and may serve as a useful prognostic marker in PDAC.

DOI： 10.1007/s00428-021-03230-2

Web of Science

PubMed

Metastatic Voyage of Ovarian Cancer Cells in Ascites with the Assistance of Various Cellular Components. Reviewed International journal

Kaname Uno, Shohei Iyoshi, Masato Yoshihara, Kazuhisa Kitami, Kazumasa Mogi, Hiroki Fujimoto, Mai Sugiyama, Yoshihiro Koya, Yoshihiko Yamakita, Akihiro Nawa, Tomohiro Kanayama, Hiroyuki Tomita, Atsushi Enomoto, Hiroaki Kajiyama

International journal of molecular sciences Vol. 23 ( 8 ) 2022.4

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

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy and has a unique metastatic route using ascites, known as the transcoelomic root. However, studies on ascites and contained cellular components have not yet been sufficiently clarified. In this review, we focus on the significance of accumulating ascites, contained EOC cells in the form of spheroids, and interaction with non-malignant host cells. To become resistant against anoikis, EOC cells form spheroids in ascites, where epithelial-to-mesenchymal transition stimulated by transforming growth factor-β can be a key pathway. As spheroids form, EOC cells are also gaining the ability to attach and invade the peritoneum to induce intraperitoneal metastasis, as well as resistance to conventional chemotherapy. Recently, accumulating evidence suggests that EOC spheroids in ascites are composed of not only cancer cells, but also non-malignant cells existing with higher abundance than EOC cells in ascites, including macrophages, mesothelial cells, and lymphocytes. Moreover, hetero-cellular spheroids are demonstrated to form more aggregated spheroids and have higher adhesion ability for the mesothelial layer. To improve the poor prognosis, we need to elucidate the mechanisms of spheroid formation and interactions with non-malignant cells in ascites that are a unique tumor microenvironment for EOC.

DOI： 10.3390/ijms23084383

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PubMed

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

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

Scientific reports Vol. 12 ( 1 ) page： 5389 - 5389 2022.3

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

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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PubMed

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

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

Pathology international Vol. 72 ( 3 ) page： 161 - 175 2022.3

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

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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PubMed

The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis. Reviewed International journal

Hiroki Kobayashi, Krystyna A Gieniec, Tamsin R M Lannagan, Tongtong Wang, Naoya Asai, Yasuyuki Mizutani, Tadashi Iida, Ryota Ando, Elaine M Thomas, Akihiro Sakai, Nobumi Suzuki, Mari Ichinose, Josephine A Wright, Laura Vrbanac, Jia Q Ng, Jarrad Goyne, Georgette Radford, Matthew J Lawrence, Tarik Sammour, Yoku Hayakawa, Sonja Klebe, Alice E Shin, Samuel Asfaha, Mark L Bettington, Florian Rieder, Nicholas Arpaia, Tal Danino, Lisa M Butler, Alastair D Burt, Simon J Leedham, Anil K Rustgi, Siddhartha Mukherjee, Masahide Takahashi, Timothy C Wang, Atsushi Enomoto, Susan L Woods, Daniel L Worthley

Gastroenterology Vol. 162 ( 3 ) page： 890 - 906 2022.3

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

BACKGROUND & AIMS: Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CAFs associated with poor prognosis. METHODS: To elucidate CAF origins, we used a colitis-associated CRC mouse model in 5 different fate-mapping mouse lines with 5-bromodeoxyuridine dosing. RNA sequencing of fluorescence-activated cell sorting-purified CRC CAFs was performed to identify a potential therapeutic target in CAFs. To examine the prognostic significance of the stromal target, CRC patient RNA sequencing data and tissue microarray were used. CRC organoids were injected into the colons of knockout mice to assess the mechanism by which the stromal gene contributes to colorectal tumorigenesis. RESULTS: Our lineage-tracing studies revealed that in CRC, many ACTA2+ CAFs emerge through proliferation from intestinal pericryptal leptin receptor (Lepr)+ cells. These Lepr-lineage CAFs, in turn, express melanoma cell adhesion molecule (MCAM), a CRC stroma-specific marker that we identified with the use of RNA sequencing. High MCAM expression induced by transforming growth factor β was inversely associated with patient survival in human CRC. In mice, stromal Mcam knockout attenuated orthotopically injected colorectal tumoroid growth and improved survival through decreased tumor-associated macrophage recruitment. Mechanistically, fibroblast MCAM interacted with interleukin-1 receptor 1 to augment nuclear factor κB-IL34/CCL8 signaling that promotes macrophage chemotaxis. CONCLUSIONS: In colorectal carcinogenesis, pericryptal Lepr-lineage cells proliferate to generate MCAM+ CAFs that shape the tumor-promoting immune microenvironment. Preventing the expansion/differentiation of Lepr-lineage CAFs or inhibiting MCAM activity could be effective therapeutic approaches for CRC.

DOI： 10.1053/j.gastro.2021.11.037

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Meflin-positive cancer-associated fibroblasts enhance tumor response to immune checkpoint blockade. Reviewed International journal

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

Life science alliance Vol. 5 ( 6 ) 2022.3

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

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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PubMed

骨肉腫におけるGPIアンカー型膜タンパク質CD109の発現とその機能解析

三井伸二, 森田悠聖, 大河内凱翔, 下山芳江, 高橋雅英, 榎本篤

日本病理学会会誌 Vol. 111 ( 1 ) page： 293 - 293 2022.3

Insulinoma-associated protein 1(INSM1) expression in breast carcinomas with neuroendocrine morphologies: application and future prospective(和訳中) Reviewed

川崎朋範, 田島知明, 良沢昭銘, 藤本章博, 堀田洋介, 宇佐見陽子, 馬場康貴, 藤田曜, 椙田浩文, 櫻本信一, 濱口哲弥, 石田博徳, 中平光彦, 佐藤弘, 平能康充, 岡本光順, 各務博, 今井久雄, 中村泰大, 解良恭一, 星田義彦, 寺本典弘, 村田有也, 伊東正博, 川島篤弘, 岩下寿秀, 立山義朗, 谷山大樹, 倉岡和矢, 谷山清己, 永井宏和, 村松千左子, 齋藤正夫, 榎本篤, 近藤哲夫, NEN project team

日本内分泌学会雑誌 Vol. 97 ( 5 ) page： 1611 - 1611 2022.3

Insulinoma-associated protein 1 expression in breast carcinomas with neuroendocrine morphologies(和訳中) Reviewed

川崎朋範, 解良恭一, 田島知明, 中村泰大, 近藤哲夫, 榎本篤, 村田有也, 星田義彦, 寺本典弘, 谷山清己, NENprojectteam

日本病理学会会誌 Vol. 111 ( 1 ) page： 254 - 254 2022.3

神経内分泌形態を伴う乳癌におけるインスリノーマ関連タンパク質1(INSM1)の発現応用と将来展望(Insulinoma-associated protein 1(INSM1) expression in breast carcinomas with neuroendocrine morphologies: application and future prospective)

日本内分泌学会雑誌 Vol. 97 ( 5 ) page： 1611 - 1611 2022.3

神経内分泌細胞の形態を持つ乳がんにおけるインスリノーマ関連タンパク質1の発現(Insulinoma-associated protein 1 expression in breast carcinomas with neuroendocrine morphologies)

川崎朋範, 解良恭一, 田島知明, 中村泰大, 近藤哲夫, 榎本篤, 村田有也, 星田義彦, 寺本典弘, 谷山清己, NEN project team

日本病理学会会誌 Vol. 111 ( 1 ) page： 254 - 254 2022.3

Safety and efficacy of MIKE-1 in patients with advanced pancreatic cancer: a study protocol for an open-label phase I/II investigator-initiated clinical trial based on a drug repositioning approach that reprograms the tumour stroma. Reviewed International journal

Yasuyuki Mizutani, Tadashi Iida, Eizaburo Ohno, Takuya Ishikawa, Fumie Kinoshita, Yachiyo Kuwatsuka, Miwa Imai, Shinobu Shimizu, Toshihisa Tsuruta, Atsushi Enomoto, Hiroki Kawashima, Mitsuhiro Fujishiro

BMC cancer Vol. 22 ( 1 ) page： 205 - 205 2022.2

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

BACKGROUND: Cancer-associated fibroblasts (CAFs) are an important component of the tumour microenvironment. Recent studies revealed CAFs are heterogeneous and CAF subset(s) that suppress cancer progression (cancer-restraining CAFs [rCAFs]) must exist in addition to well-characterised cancer-promoting CAFs (pCAFs). However, the identity and specific markers of rCAFs are not yet reported. We recently identified Meflin as a specific marker of rCAFs in pancreatic and colon cancers. Our studies revealed that rCAFs may represent proliferating resident fibroblasts. Interestingly, a lineage tracing experiment showed Meflin-positive rCAFs differentiate into α-smooth muscle actin-positive and Meflin-negative CAFs, which are generally hypothesised as pCAFs, during cancer progression. Using a pharmacological approach, we identified AM80, a synthetic unnatural retinoid, as a reagent that effectively converts Meflin-negative pCAFs to Meflin-positive rCAFs. We aimed to investigate the efficacy of a combination of AM80 and gemcitabine (GEM) and nab-paclitaxel (nab-PTX) in patients with advanced pancreatic cancer. METHODS: The phase I part is a 3 + 3 design, open-label, and dose-finding study. The dose-limiting toxicity (DLT) of these combination therapies would be evaluated for 4 weeks. After the DLT evaluation period, if no disease progression is noted based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or if the patient has no intolerable toxicity, administration of AM80 with GEM and nab-PTX would be continued for up to 24 weeks. The phase II part is an open-label, single-arm study. The maximum tolerated dose (MTD) of AM80 with GEM and nab-PTX, determined in phase I, would be administered until intolerable toxicity or disease progression occurs, up to a maximum of 24 weeks, to confirm efficacy and safety. The primary endpoints are frequency of DLT and MTD of AM80 with GEM and nab-PTX in the phase I part and response rate based on the RECIST in the phase II part. Given the historical control data, we hope that the response rate will be over 23% in phase II. DISCUSSION: Strategies to convert pCAFs into rCAFs have been developed in recent years. We hypothesised that AM80 would be a promising enhancer of chemosensitivity and drug distribution through CAF conversion in the stroma. TRIAL REGISTRATION: Clinicaltrial.gov: NCT05064618 , registered on 1 October 2021. jRCT: jRCT2041210056 , registered on 27 August 2021.

DOI： 10.1186/s12885-022-09272-2

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PubMed

Metabolically distinct glioma stem cells differentially require Girdin for stem cell behavior and tumor development

Watanabe, T; Yanagi, H; Enomoto, A; Sampetrean, O; Saya, H; Shimono, Y

CANCER SCIENCE Vol. 113 page： 988 - 988 2022.2

Fibroblasts positive for meflin have anti-fibrotic properties in pulmonary fibrosis. Reviewed International journal

Yoshio Nakahara, Naozumi Hashimoto, Koji Sakamoto, Atsushi Enomoto, Taylor S Adams, Toyoharu Yokoi, Norihito Omote, Sergio Poli, Akira Ando, Keiko Wakahara, Atsushi Suzuki, Masahide Inoue, Akitoshi Hara, Yasuyuki Mizutani, Kazuyoshi Imaizumi, Tsutomu Kawabe, Ivan O Rosas, Masahide Takahashi, Naftali Kaminski, Yoshinori Hasegawa

The European respiratory journal Vol. 58 ( 6 ) 2021.12

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

The prognosis of elderly individuals with idiopathic pulmonary fibrosis (IPF) remains poor. Fibroblastic foci, in which aggregates of proliferating fibroblasts and myofibroblasts are involved, are the pathological hallmark lesions in IPF to represent focal areas of active fibrogenesis. Fibroblast heterogeneity in fibrotic lesions hampers the discovery of the pathogenesis of pulmonary fibrosis. Therefore, to determine of the pathogenesis of IPF, identification of functional fibroblasts is warranted. This study was aimed to determine the role of fibroblasts positive for meflin, identified as a potential marker for mesenchymal stromal cells, during the development of pulmonary fibrosis. We characterised meflin-positive cells in a single cell atlas established by single-cell RNA sequencing (scRNA-seq)-based profiling of 243 472 cells from 32 IPF lungs and 29 normal lung samples. scRNA-seq combined with in situ RNA hybridisation identified proliferating fibroblasts positive for meflin in fibroblastic foci, not dense fibrosis, of fibrotic lungs in IPF patients. We determined the role of fibroblasts positive for meflin using bleomycin (BLM)-induced pulmonary fibrosis. A BLM-induced lung fibrosis model for meflin-deficient mice showed that fibroblasts positive for meflin had anti-fibrotic property to prevent pulmonary fibrosis. Although transforming growth factor-β-induced fibrogenesis and cell senescence with senescence-associated secretory phenotype were exacerbated in fibroblasts via the repression or lack of meflin, these were inhibited in meflin-deficient fibroblasts with meflin reconstitution. These findings provide evidence to show the biological importance of meflin expression on fibroblasts and myofibroblasts in the active fibrotic region of pulmonary fibrosis.

DOI： 10.1183/13993003.03397-2020

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Anti-Malignant Effect of Tensile Loading to Adherens Junctions in Cutaneous Squamous Cell Carcinoma Cells. Reviewed International journal

Oleg Dobrokhotov, Masaki Sunagawa, Takeru Torii, Shinji Mii, Keiko Kawauchi, Atsushi Enomoto, Masahiro Sokabe, Hiroaki Hirata

Frontiers in cell and developmental biology Vol. 9 page： 728383 - 728383 2021.11

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

Actomyosin contractility regulates various cellular processes including proliferation and differentiation while dysregulation of actomyosin activity contributes to cancer development and progression. Previously, we have reported that actomyosin-generated tension at adherens junctions is required for cell density-dependent inhibition of proliferation of normal skin keratinocytes. However, it remains unclear how actomyosin contractility affects the hyperproliferation ability of cutaneous squamous cell carcinoma (cSCC) cells. In this study, we find that actomyosin activity is impaired in cSCC cells both in vitro and in vivo. External application of tensile loads to adherens junctions by sustained mechanical stretch attenuates the proliferation of cSCC cells, which depends on intact adherens junctions. Forced activation of actomyosin of cSCC cells also inhibits their proliferation in a cell-cell contact-dependent manner. Furthermore, the cell cycle arrest induced by tensile loading to adherens junctions is accompanied by epidermal differentiation in cSCC cells. Our results show that the degree of malignant properties of cSCC cells can be reduced by applying tensile loads to adherens junctions, which implies that the mechanical status of adherens junctions may serve as a novel therapeutic target for cSCC.

DOI： 10.3389/fcell.2021.728383

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Newly established patient-derived organoid model of intracranial meningioma. Reviewed International journal

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

Neuro-oncology Vol. 23 ( 11 ) page： 1936 - 1948 2021.11

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

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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Ring artifact removal for differential phase-contrast X-ray computed tomography using a conditional generative adversarial network. Reviewed International journal

Zhuoran Huang, Naoki Sunaguchi, Daisuke Shimao, Atsushi Enomoto, Shu Ichihara, Tetsuya Yuasa, Masami Ando

International journal of computer assisted radiology and surgery Vol. 16 ( 11 ) page： 1889 - 1900 2021.11

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

PURPOSE: The integration process used as a pre-processing step in the reconstruction of differential phase-contrast X-ray CT (d-PCCT) causes the measurement noise to propagate throughout the projection image, which is leading to increased ring artifacts (RA) in the reconstructed image. It is difficult to eliminate the RA using conventional RA removal methods that were developed for the absorption-based CT field. We propose an effective method that can remove RA of d-PCCT images. METHODS: The proposed method uses Laplacian images reconstructed from second-derivative projections of d-PCCT. This method is based on a conditional generative adversarial network (cGAN), whose loss function is designed by adding the L1- and L2-norm to the original cGAN. The training data were taken from a numerical phantom generated by a d-PCCT imaging simulator. To validate the applicability of the trained network, we tested its RA removal effect on test data from numerical phantoms generated randomly and actual experimental data. RESULTS: The results of numerical validation using numerical phantoms showed that the proposed method improved the RA removal effect compared to conventional methods. In addition, image comparison by visual evaluation showed that only the proposed method was able to remove RA while preserving original structures in the actual biological d-PCCT images. CONCLUSION: We proposed a cGAN-based method for RA removal that exploits the physical properties of d-PCCT. The proposed method was able to completely remove RA from d-PCCT images on both simulated data and biological data. We believe that this method is useful for the observation of various types of biological soft tissue.

DOI： 10.1007/s11548-021-02500-3

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Roles of the Mesenchymal Stromal/Stem Cell Marker Meflin/Islr in Cancer Fibrosis. Reviewed International journal

Masahide Takahashi, Hiroki Kobayashi, Yasuyuki Mizutani, Akitoshi Hara, Tadashi Iida, Yuki Miyai, Naoya Asai, Atsushi Enomoto

Frontiers in cell and developmental biology Vol. 9 page： 749924 - 749924 2021.10

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

Fibroblasts synthesise the extracellular matrix (ECM) such as collagen and elastin, the excessive accumulation of which can lead to fibrosis and organ dysfunction under pathological conditions. Cancer-associated fibroblasts (CAFs) are major constituents of the tumour microenvironment (TME) that accompany the desmoplastic reaction responsible for anti-cancer treatment resistance. Thus, it is important to dissect the roles of CAFs in the TME to develop new therapeutic strategies for refractory cancers. Recent progress in the studies of CAF biology suggests that the functions of CAFs are complicated and that they are composed of functionally distinct populations, including cancer-promoting CAFs (pCAFs) and cancer-restraining CAFs (rCAFs). We recently identified a new cell surface marker for rCAFs in pancreatic and colon cancers, designated as Meflin (mesenchymal stromal cell- and fibroblast-expressing Linx paralogue)/Islr (immunoglobulin super family containing leucine-rich repeat). Based on the distribution of Meflin/Islr-positive cells, we also considered it a specific candidate marker for mesenchymal stroma/stem cells. Meflin/Islr-positive CAFs have been shown to suppress cancer progression by being involved in regulating collagen structures and BMP signalling in the TME. This review describes the function of Meflin/Islr in cancer fibrosis as well as in cardiac and lung fibrosis and its potential in the development of new cancer therapeutics.

DOI： 10.3389/fcell.2021.749924

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Portal Vein Injection of Colorectal Cancer Organoids to Study the Liver Metastasis Stroma. Reviewed International journal

Hiroki Kobayashi, Krystyna A Gieniec, Jia Q Ng, Jarrad Goyne, Tamsin R M Lannagan, Elaine M Thomas, Georgette Radford, Tongtong Wang, Nobumi Suzuki, Mari Ichinose, Josephine A Wright, Laura Vrbanac, Alastair D Burt, Masahide Takahashi, Atsushi Enomoto, Daniel L Worthley, Susan L Woods

Journal of visualized experiments : JoVE ( 175 ) 2021.9

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

Hepatic metastasis of colorectal cancer (CRC) is a leading cause of cancer-related death. Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment, play a crucial role in metastatic CRC progression and predict poor patient prognosis. However, there is a lack of satisfactory mouse models to study the crosstalk between metastatic cancer cells and CAFs. Here, we present a method to investigate how liver metastasis progression is regulated by the metastatic niche and possibly could be restrained by stroma-directed therapy. Portal vein injection of CRC organoids generated a desmoplastic reaction, which faithfully recapitulated the fibroblast-rich histology of human CRC liver metastases. This model was tissue-specific with a higher tumor burden in the liver when compared to an intra-splenic injection model, simplifying mouse survival analyses. By injecting luciferase-expressing tumor organoids, tumor growth kinetics could be monitored by in vivo imaging. Moreover, this preclinical model provides a useful platform to assess the efficacy of therapeutics targeting the tumor mesenchyme. We describe methods to examine whether adeno-associated virus-mediated delivery of a tumor-inhibiting stromal gene to hepatocytes could remodel the tumor microenvironment and improve mouse survival. This approach enables the development and assessment of novel therapeutic strategies to inhibit hepatic metastasis of CRC.

DOI： 10.3791/62630

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Girdinは代謝特性の異なるグリオーマ幹細胞の幹細胞性、腫瘍形成を特徴的な様式で制御する

渡辺崇, 柳久乃, 榎本篤, サンペトラ・オルテア, 佐谷秀行, 下野洋平

日本癌学会総会記事 Vol. 80回 page： [P11 - 2] 2021.9

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Papers - ENOMOTO, Atsushi