Updated on 2024/12/27

Information

 

写真a

 
IWAMOTO CHIKA
 
Organization
Faculty of Medical Sciences Department of Clinical Medicine Assistant Professor
School of Medicine Department of Medicine(Concurrent)
Title
Assistant Professor
Profile
自身の研究プロジェクトや分担の研究プロジェクトの遂行、医学研究院医学専攻博士過程の大学院生の研究指導も行っている。 非常勤講師として外部研究施設での実験指導も行っている。
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Degree

  • PhD

Research Interests・Research Keywords

  • Research theme:The potential role of genetic mutations iniImmune cells in pancreatic cancer

    Keyword:PDAC, microenvironment, mutation

    Research period: 2024.4 - 2027.3

  • Research theme:Elucidation of the mechanism of macrophage immune checkpoint in pancreatic cancer

    Keyword:pancreatic cancer, macrophage, microenvironment

    Research period: 2021.4 - 2024.3

Awards

  • American Pancreatic Association Poster of Distinction

    2023.11   APA  

  • American Pancreatic Association Poster of Distinction

    2019.8   APA  

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    Background: The tumor microenvironment is diverse depending on the carcinoma. In gastric cancer, it has been reported that bone marrow (BM)-derived cells invade tumor tissues by local inflammatory reaction, form inflammatory microenvironment and produce cytokines and growth factors, leading to promoting carcinogenesis. In pancreatic cancer, mesenchymal stem cells-derived tumor stroma seems to promote tumor development. However, involvement of BM-derived cells on tumor progression and its mechanism remains unclear. We aimed to investigate its involvement in the remodeling of microenvironment and pancreatic cancer progression.
    Methods & Results: Mouse models of allogeneic BM transplantation using newborn KC/ KPC mice were established. KC recipients’ pancreas didn’t turn cancerous, but BM-derived GFP+ cells were engrafted around acinar cells with atrophy. In KPC recipients’ pancreas, BM-derived multilineage hematopoietic cells were accumulated at invasive front, and especially the localization of macrophages including TAM or aSMA+ cells were similar to GFP+ cells. Then, human pancreatic cancer cells (PCCs) co-injected with peripheral blood (PB)-derived macrophages grew invasively in xenotransplantation models. PB-derived macrophages destructed basement membrane than pancreatic stellate cells (PSCs). We investigated the involvement of PB-derived macrophages in the invasive capability of PCCs, and found that the specific subpopulation of those cells led the invasion of PCCs similar to PSCs known as a leading cell in the invasion. Some PB-derived macrophages treated with PCCs supernatant expressed PSC marker.
    Conclusion: The present data suggest that BM-derived cells recruited to pancreas in the pancreatic carcinogenesis are involved in invasion of PCCs, and also that the specific subpopulation of BM-derived macrophages transformed into PSC-like cells and acted as leading cells in the invasion of pancreatic cancer.

  • American Pancreatic Association Young Investigator Travel Award

    2019.8   APA  

  • 膵臓病研究奨励賞

    2018.12   日本膵臓病研究財団  

  • Scientific Accomplishment As An Early Career Investigator

    2018.6   DDW  

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    Introduction: Cancer malignancy increase due to tumor-stroma interactions, whereas cytokines secreted by cancer cells differentiate activated macrophages into tumor associated macrophages (TMAs), which produce angiogenesis factor and cell growth factor to form the tumor microenvironment. In breast cancer, stromal cells, which support cancer cell proliferation and lead cancer cell invasion, were reported to be descended from bone marrow (BM)-derived mesenchymal stem cells. Although BM-derived cells seem to be involved in remodeling of microenvironment and tumor progression in pancreatic cancer, this mechanism remains incompletely understood. We aimed to investigate an association between pancreatic cancer progression and BM-derived cells using KPC mice.
    Methods: To develop the allogeneic BM transplantation models in KPC mice, BM-derived GFP+ cells were intravenously transplanted into KPC mice following sublethal irradiation. The phenotypical characterization of engrafted GFP+ cells was analyzed by flow cytometry (FCM). Derivation of stromal cells associated with tumor-stroma interactions and distribution of TAMs constituting the tumor microenvironment were examined using immunohistochemical staining. To evaluate invasive capacity and proliferation activity of pancreatic cancer cells (PCCs) co-cultured with BM-derived cells, we performed cell invasion assay and cell viability assay.
    Results: The engraftment of BM-derived GFP+ cells was detected in recipients’ peripheral blood, BM, pancreas, liver, and ascites by FCM. The engrafted GFP+ cells expressed CD45 consisting of a few CD4+/ CD8+ T cells, a few NK cells, or macrophages. The efficiency of macrophages engraftment in recipient KPC mice was higher than that of the control. In recipients’ pancreas, GFP+ cells, F4/80+ macrophages, and CD163+ TAMs were accumulated around ADM, PanIN, stroma cells, and at invasive front. None of BM-derived macrophages and TAMs inhabited around normal acinar cells. Invasive capacity of cancer cells co-cultured with BM-derived macrophages significantly increased compared to the control (p<0.05). Distribution of BM-derived GFP+ cells tends to be similar to that of aSMA+ cells, and a few GFP+aSMA+ cells were detected.
    Conclusion: BM-derived lymphocytes, macrophages, and TAMs were engrafted in recipients’ pancreas, and their distribution was biased. The present data suggest that BM-derived cells are involved in the tumor microenvironment constitution and infiltration of PCCs.

  • American Society of Hematology Abstract Achievement Award

    2011.10  

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Papers

  • Dynamic glycolytic reprogramming effects on dendritic cells in pancreatic ductal adenocarcinoma.

    Zhang B, Ohuchida K, Tsutsumi C, Shimada Y, Mochida Y, Oyama K, Iwamoto C, Sheng N, Fei S, Shindo K, Ikenaga N, Nakata K, Oda Y, Nakamura M

    Journal of experimental & clinical cancer research : CR   43 ( 1 )   271   2024.9   ISSN:0392-9078

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    DOI: 10.1186/s13046-024-03192-8

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  • Combined Autophagy Inhibition and Dendritic Cell Recruitment Induces Antitumor Immunity and Enhances Immune Checkpoint Blockade Sensitivity in Pancreatic Cancer.

    Oyama K, Nakata K, Tsutsumi C, Hayashi M, Zhang B, Mochida Y, Shinkawa T, Hirotaka K, Zhong P, Date S, Luo H, Kubo A, Higashijima N, Yamada Y, Abe T, Ideno N, Koikawa K, Iwamoto C, Ikenaga N, Ohuchida K, Onishi H, Morisaki T, Kuba K, Oda Y, Nakamura M

    Cancer research   2024.9   ISSN:0008-5472

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    DOI: 10.1158/0008-5472.CAN-24-0830

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  • Tumor-associated neutrophils upregulate Nectin2 expression, creating the immunosuppressive microenvironment in pancreatic ductal adenocarcinoma

    Luo, HZ; Ikenaga, N; Nakata, K; Higashijima, N; Zhong, PS; Kubo, A; Wu, CY; Tsutsumi, C; Shimada, Y; Hayashi, M; Oyama, K; Date, S; Abe, T; Ideno, N; Iwamoto, C; Shindo, K; Ohuchida, K; Oda, Y; Nakamura, M

    JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH   43 ( 1 )   258   2024.9   ISSN:0392-9078 eISSN:1756-9966

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    Language:English   Publisher:Journal of Experimental and Clinical Cancer Research  

    Background: Tumor-associated neutrophils (TANs) constitute an abundant component among tumor-infiltrating immune cells and have recently emerged as a critical player in pancreatic ductal adenocarcinoma (PDAC) progression. This study aimed to elucidate the pro-tumor mechanisms of TAN and identify a novel target for effective immunotherapy against PDAC. Methods: Microarray and cytokine array analyses were performed to identify the mechanisms underlying the function of TANs. Human and mouse TANs were obtained from differentiated HL-60 cells and orthotopically transplanted PDAC tumors, respectively. The interactions of TANs with cancer and cytotoxic T-cells were evaluated through in vitro co-culture and in vivo orthotopic or subcutaneous models. Single-cell transcriptomes from patients with PDAC were analyzed to validate the cellular findings. Results: Increased neutrophil infiltration in the tumor microenvironment was associated with poor survival in patients with PDAC. TANs secreted abundant amounts of chemokine ligand 5 (CCL5), subsequently enhancing cancer cell migration and invasion. TANs subpopulations negatively correlated with cytotoxic CD8+ T-cell infiltration in PDAC and promoted T-cell dysfunction. TANs upregulated the membranous expression of Nectin2, which contributed to CD8+ T-cell exhaustion. Blocking Nectin2 improved CD8+ T-cell function and suppressed tumor progression in the mouse model. Single-cell analysis of human PDAC revealed two immunosuppressive TANs phenotypes: Nectin2+ TANs and OLR1+ TANs. Endoplasmic reticulum stress regulated the protumor activities in TANs. Conclusions: TANs enhance PDAC progression by secreting CCL5 and upregulating Nectin2. Targeting the immune checkpoint Nectin2 could represent a novel strategy to enhance immunotherapy efficacy in PDAC.

    DOI: 10.1186/s13046-024-03178-6

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  • Microbiome in the Therapy for the Pancreatic Cancer

    Ikenaga N., Hayashi M., Matsuyoshi T., Iwamoto C., Nakata K., Ohuchida K., Nakamura M.

    Gan to kagaku ryoho. Cancer &amp; chemotherapy   51 ( 6 )   603 - 607   2024.6   ISSN:03850684

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    Publisher:Gan to kagaku ryoho. Cancer &amp; chemotherapy  

    An association between periodontal disease and the development of pancreatic cancer has been pointed out since before. Advances in genome analysis technology have revealed that a pancreatic cancer-specific microbiome is formed in the intestines and tumors of pancreatic cancer patients and modifies the progression of pancreatic cancer. Disturbance of microbiome( dysbiosis)suppresses anti-tumor immunity against pancreatic cancer, promoting cancer progression. Therefore, attempts are being made to correct dysbiosis by administration of probiotics or transplantation of microbiome, which is especially activating immune checkpoint inhibitors against cancer. In addition, specific intratumor bacteria has been identified that create an immunosuppressive microenvironment through crosstalk with pancreatic cancer cells. In the future, analysis of the microbiome distribution in pancreatic cancers may determine the following treatment strategy as an individualized treatment. We hope that innovations in omics technology will reveal more detailed functions of microbiome and lead to the development of effective treatments for pancreatic cancer.

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  • [Microbiome in the Therapy for the Pancreatic Cancer].

    Ikenaga N, Hayashi M, Matsuyoshi T, Iwamoto C, Nakata K, Ohuchida K, Nakamura M

    Gan to kagaku ryoho. Cancer & chemotherapy   51 ( 6 )   603 - 607   2024.6   ISSN:0385-0684

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  • Blockade of histamine receptor H1 augments immune checkpoint therapy by enhancing MHC-I expression in pancreatic cancer cells

    Zhong, P; Nakata, K; Oyama, K; Higashijima, N; Sagara, A; Date, S; Luo, HZ; Hayashi, M; Kubo, A; Wu, CY; He, S; Yamamoto, T; Koikawa, K; Iwamoto, C; Abe, T; Ikenaga, N; Ohuchida, K; Morisaki, T; Oda, Y; Kuba, K; Nakamura, M

    JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH   43 ( 1 )   138   2024.5   ISSN:0392-9078 eISSN:1756-9966

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    Language:English   Publisher:Journal of Experimental and Clinical Cancer Research  

    Background: Although immune checkpoint blockade (ICB) therapy has proven to be extremely effective at managing certain cancers, its efficacy in treating pancreatic ductal adenocarcinoma (PDAC) has been limited. Therefore, enhancing the effect of ICB could improve the prognosis of PDAC. In this study, we focused on the histamine receptor H1 (HRH1) and investigated its impact on ICB therapy for PDAC. Methods: We assessed HRH1 expression in pancreatic cancer cell (PCC) specimens from PDAC patients through public data analysis and immunohistochemical (IHC) staining. The impact of HRH1 in PCCs was evaluated using HRH1 antagonists and small hairpin RNA (shRNA). Techniques including Western blot, flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-PCR), and microarray analyses were performed to identify the relationships between HRH1 and major histocompatibility complex class I (MHC-I) expression in cancer cells. We combined HRH1 antagonism or knockdown with anti-programmed death receptor 1 (αPD-1) therapy in orthotopic models, employing IHC, immunofluorescence, and hematoxylin and eosin staining for assessment. Results: HRH1 expression in cancer cells was negatively correlated with HLA-ABC expression, CD8+ T cells, and cytotoxic CD8+ T cells. Our findings indicate that HRH1 blockade upregulates MHC-I expression in PCCs via cholesterol biosynthesis signaling. In the orthotopic model, the combined inhibition of HRH1 and αPD-1 blockade enhanced cytotoxic CD8+ T cell penetration and efficacy, overcoming resistance to ICB therapy. Conclusions: HRH1 plays an immunosuppressive role in cancer cells. Consequently, HRH1 intervention may be a promising method to amplify the responsiveness of PDAC to immunotherapy.

    DOI: 10.1186/s13046-024-03060-5

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  • Tumor-infiltrating monocytic myeloid-derived suppressor cells contribute to the development of an immunosuppressive tumor microenvironment in gastric cancer(タイトル和訳中)

    Tsutsumi Chikanori, Ohuchida Kenoki, Katayama Naoki, Yamada Yutaka, Nakamura Shoichi, Okuda Sho, Otsubo Yoshiki, Iwamoto Chika, Torata Nobuhiro, Horioka Kohei, Shindo Koji, Mizuuchi Yusuke, Ikenaga Naoki, Nakata Kohei, Nagai Eishi, Morisaki Takashi, Oda Yoshinao, Nakamura Masafumi

    Gastric Cancer   27 ( 2 )   248 - 262   2024.3   ISSN:1436-3291

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    Language:English   Publisher:シュプリンガー・ジャパン(株)  

  • Tumor-infiltrating monocytic myeloid-derived suppressor cells contribute to the development of an immunosuppressive tumor microenvironment in gastric cancer

    Tsutsumi, C; Ohuchida, K; Katayama, N; Yamada, Y; Nakamura, S; Okuda, S; Otsubo, Y; Iwamoto, C; Torata, N; Horioka, K; Shindo, K; Mizuuchi, Y; Ikenaga, N; Nakata, K; Nagai, E; Morisaki, T; Oda, Y; Nakamura, M

    GASTRIC CANCER   27 ( 2 )   248 - 262   2024.3   ISSN:1436-3291 eISSN:1436-3305

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    Language:English   Publisher:Gastric Cancer  

    Background: Gastric cancer (GC) is characterized by an immunosuppressive and treatment-resistant tumor immune microenvironment (TIME). Here, we investigated the roles of different immunosuppressive cell types in the development of the GC TIME. Methods: Single-cell RNA sequencing (scRNA-seq) and multiplex immunostaining of samples from untreated or immune checkpoint inhibitor (ICI)-resistant GC patients were used to examine the correlation between certain immunosuppressive cells and the prognosis of GC patients. Results: The results of the scRNA-seq analysis revealed that tumor-infiltrating monocytic myeloid-derived suppressor cells (TI-M-MDSCs) expressed higher levels of genes with immunosuppressive functions than other immunosuppressive cell types. Additionally, M-MDSCs in GC tissues expressed significantly higher levels of these markers than adjacent normal tissues. The M-MDSCs were most enriched in GC tissues relative to adjacent normal tissues. Among the immunosuppressive cell types assessed, the M-MDSCs were most enriched in GC tissues relative to adjacent normal tissues; moreover, their presence was most strongly associated with a poor prognosis. Immediate early response 3 (IER3), which we identified as a differentially expressed gene between M-MDSCs of GC and adjacent normal tissues, was an independent poor prognostic factor in GC patients (P = 0.0003). IER3+ M-MDSCs expressed higher levels of genes with immunosuppressive functions than IER3− M-MDSCs and were abundant in treatment-resistant GC patients. Conclusions: The present study suggests that TI-M-MDSCs, especially IER3+ ones, may play a predominant role in the development of the immunosuppressive and ICI-resistant GC TIME.

    DOI: 10.1007/s10120-023-01456-4

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  • Tertiary lymphoid structures correlate with enhancement of antitumor immunity in esophageal squamous cell carcinoma

    Nakamura, S; Ohuchida, K; Hayashi, M; Katayama, N; Tsutsumi, C; Yamada, Y; Hisano, K; Okuda, S; Ohtsubo, Y; Iwamoto, C; Torata, N; Mizuuchi, Y; Shindo, K; Nakata, K; Moriyama, T; Morisaki, T; Oda, Y; Nakamura, M

    BRITISH JOURNAL OF CANCER   129 ( 8 )   1314 - 1326   2023.10   ISSN:0007-0920 eISSN:1532-1827

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    Language:English   Publisher:British Journal of Cancer  

    Background: Tertiary lymphoid structures (TLSs) are associated with a favorable prognosis in several cancers. However, the correlation between TLSs and outcomes of esophageal squamous cell carcinoma (ESCC) and the impact of TLSs on the tumor immune microenvironment (TIME) remain unknown. Methods: We pathologically evaluated the significance of TLSs in ESCC focusing on TLS maturation using 180 ESCC specimens and performed single-cell RNA sequencing (scRNA-seq) using 14 ESCC tissues to investigate functional differences of immune cells according to TLS presence. Results: TLS+ cases had better recurrence-free-survival (RFS) (p < 0.0001) and overall survival (OS) (p = 0.0016) compared with TLS- cases. Additionally, mature TLS+ cases had better RFS and OS compared with immature TLS+ cases (p = 0.019 and p = 0.015) and TLS- cases (p < 0.0001 and p = 0.0002). The scRNA-seq showed that CD8+ T cells in TLS+ tumors expressed high levels of cytotoxic signatures and antigen-presentation of dendritic cells (DCs) was enhanced in TLS+ tumors. Immunohistochemistry showed that the densities of tumor-infiltrating CD8+ T cells and DCs were significantly higher in TLS+ tumors than those in TLS- tumors. Conclusions: These data suggest the prognostic and functional significance of TLSs in ESCC and provides new insights into TLSs on the TIME.

    DOI: 10.1038/s41416-023-02396-7

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  • 膵癌組織内のFusobacterium nucleatumはCXCL1-CXCR2シグナル伝達軸を介して膵癌の進行を促進する(Intratumor Fusobacterium nucleatum promotes the progression of pancreatic cancer via the CXCL1-CXCR2 axis)

    Hayashi Masataka, Ikenaga Naoki, Nakata Kohei, Luo Haizhen, Zhong PingShan, Date Satomi, Oyama Koki, Higashijima Nobuhiro, Kubo Akihiro, Iwamoto Chika, Torata Nobuhiro, Abe Toshiya, Yamada Yutaka, Ohuchida Kenoki, Oda Yoshinao, Nakamura Masafumi

    Cancer Science   114 ( 9 )   3666 - 3678   2023.9   ISSN:1347-9032

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    Language:English   Publisher:John Wiley & Sons Australia, Ltd  

    歯周病原菌であるFusobacterium nucleatumは膵癌組織内でも発見されており、予後不良と関連していることが知られている。同菌は膵癌進行に重要な役割を果たしているのでないかとの仮説を検証した。膵管腺癌患者の手術検体を調べた。その結果、84名中13名(15.5%)でF.nucleatumが検出された。同菌が陽性の群では陰性の群に比べ腫瘍サイズが有意に大きかった。ヒト膵癌細胞株の培養系では、同菌と共培養することで膵癌細胞からのC-X-Cモチーフケモカインリガンド1(CXCL1)の分泌が促進されることが示された。膵癌マウスモデルの皮下に同菌を注入すると、骨髄由来抑制細胞が腫瘍へ動員されることで腫瘍浸潤T細胞が抑制され、その結果、腫瘍は進行した。骨髄由来抑制細胞を枯渇させるかサイトカイン阻害剤を使用すると、同菌による腫瘍増殖加速作用は抑制された。本研究結果をまとめると、腫瘍内のF.nucleatumは、CXCL1とC-X-Cモチーフケモカイン受容体2(CXCR2)のシグナル伝達軸によるオートクリン・パラクリンの機序を通じて、膵癌の進行を促進していた。腫瘍内にF.nucleatumがみられる膵癌患者に対し、CXCL1-CXCR2軸を遮断する方法は新規な治療アプローチになると考えられた。

  • Intratumor <i>Fusobacterium nucleatum</i> promotes the progression of pancreatic cancer via the CXCL1-CXCR2 axis

    Hayashi, M; Ikenaga, N; Nakata, K; Luo, HZ; Zhong, PS; Date, S; Oyama, K; Higashijima, N; Kubo, A; Iwamoto, C; Torata, N; Abe, T; Yamada, Y; Ohuchida, K; Oda, Y; Nakamura, M

    CANCER SCIENCE   114 ( 9 )   3666 - 3678   2023.9   ISSN:1347-9032 eISSN:1349-7006

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    Intratumor bacteria modify the tumor immune microenvironment and influence outcomes of various tumors. Periodontal pathogen Fusobacterium nucleatum has been detected in pancreatic cancer tissues and is associated with poor prognosis. However, it remains unclear how F. nucleatum affects pancreatic cancer. Here, we compared clinical features with F. nucleatum colonization in pancreatic cancer tissues. F. nucleatum was detected in 15.5% (13/84) of pancreatic cancer patients. The tumor size was significantly larger in the F. nucleatum-positive group than in the negative group. To clarify the biological effect of intratumor F. nucleatum on pancreatic cancer progression, we performed migration/invasion assays and cytokine array analysis of cancer cells cocultured with F. nucleatum. F. nucleatum promoted CXCL1 secretion from pancreatic cancer cells, leading to cancer progression through autocrine signaling. Intratumor F. nucleatum suppressed tumor-infiltrating CD8+ T cells by recruiting myeloid-derived suppressor cells (MDSCs) to the tumor in an F. nucleatum-injected subcutaneous pancreatic cancer mouse model, resulting in tumor progression. Furthermore, tumor growth accelerated by F. nucleatum was suppressed by MDSC depletion or cytokine inhibitors. Intratumor F. nucleatum promoted pancreatic cancer progression through autocrine and paracrine mechanisms of the CXCL1-CXCR2 axis. Blockade of the CXCL1-CXCR2 axis may be a novel therapeutic approach for patients with intratumor F. nucleatum-positive pancreatic cancer.

    DOI: 10.1111/cas.15901

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  • Involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia lesion of pancreatic cancer invasive front

    Fei, S; Ohuchida, K; Kibe, S; Yan, ZL; Iwamoto, C; Shinkawa, T; Zhang, B; Kawata, J; Abe, T; Ideno, N; Ikenaga, N; Nakata, K; Oda, Y; Nakamura, M

    JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY   149 ( 9 )   5885 - 5899   2023.8   ISSN:0171-5216 eISSN:1432-1335

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    Language:English   Publisher:Journal of Cancer Research and Clinical Oncology  

    Purpose: This study aimed to demonstrate the involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia (CA-ADM) lesion of invasive front pancreatic ductal adenocarcinoma (PDAC) and investigate the possible mechanism. Methods: Tissue samples from 128 patients with PDAC and 36 LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre mice were analyzed. Immunohistochemical assay was performed using HE, anti-CK19 and anti-amylase to confirm the presence of CA-ADM lesions, using anti-CD34 and anti-CD31 to measure microvessel density (MVD), and using anti-CD68, anti-CD163, anti-iNOS, or anti-MMP9 to evaluate the immune microenvironment. We performed multiplex immunohistochemical assay to detect the co-expression of MMP9 and CD68 on macrophage. We examined clinical outcomes and other clinicopathological factors to determine the significance of high-level MVD of CA-ADM on survival and liver metastasis. We performed tube formation assay to evaluate the effect of macrophage on angiogenic capacity in vitro. Results: Angiogenesis was significantly abundant in CA-ADM lesions compared with that in PDAC lesions in human and mouse tissues. High-level MVD in CA-ADM lesions was an independent predictor of poor prognosis (P = 0.0047) and the recurrence of liver metastasis (P = 0.0027). More CD68-positive and CD163-positive macrophages were detected in CA-ADM lesions than in PDAC. The percentage of CD68-positive macrophages was positively correlated with MVD in CA-ADM lesions. Multiplex-immunostaining revealed that MMP9 was expressed in CD68-positive macrophages of CA-ADM lesions. In CA-ADM lesions, the percentage of macrophages was positively correlated with MMP9 expression, which positively correlated with microvessel density. Conclusion: CA-ADM related angiogenesis is a promising predictive marker for poor prognosis of PDAC and may provide an attractive therapeutic target for PDAC.

    DOI: 10.1007/s00432-022-04554-5

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  • Neoadjuvant chemotherapy enhances anti-tumor immune response of tumor microenvironment in human esophageal squamous cell carcinoma

    Okuda, S; Ohuchida, K; Nakamura, S; Tsutsumi, C; Hisano, K; Mochida, Y; Kawata, J; Ohtsubo, Y; Shinkawa, T; Iwamoto, C; Torata, N; Mizuuchi, Y; Shindo, K; Moriyama, T; Nakata, K; Torisu, T; Morisaki, T; Kitazono, T; Oda, Y; Nakamura, M

    ISCIENCE   26 ( 4 )   106480   2023.4   eISSN:2589-0042

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    Language:English   Publisher:iScience  

    Although chemotherapy has been an essential treatment for cancer, the development of immune checkpoint blockade therapy was revolutionary, and a comprehensive understanding of the immunological tumor microenvironment (TME) has become crucial. Here, we investigated the impact of neoadjuvant chemotherapy (NAC) on immune cells in the TME of human esophageal squamous cell carcinoma using single cell RNA-sequencing. Analysis of 30 fresh samples revealed that CD8+/CD4+ T cells, dendritic cells (DCs), and macrophages in the TME of human esophageal squamous cell carcinoma showed higher levels of an anti-tumor immune response in the NAC(+) group than in the NAC(−) group. Furthermore, the immune cells of the NAC(+) group interacted with each other resulting in enhanced anti-tumor immune response via various cytokines, including IFNG in CD8+/CD4+ T cells, EBI3 in DCs, and NAMPT in macrophages. Our results suggest that NAC potentially enhances the anti-tumor immune response of immune cells in the TME.

    DOI: 10.1016/j.isci.2023.106480

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  • Single-cell transcriptome analysis reveals functional changes in tumour-infiltrating B lymphocytes after chemotherapy in oesophageal squamous cell carcinoma

    Nakamura, S; Ohuchida, K; Ohtsubo, Y; Yamada, Y; Tsutsumi, C; Okuda, S; Hisano, K; Mochida, Y; Shinkawa, T; Iwamoto, C; Torata, N; Mizuuchi, Y; Shindo, K; Nakata, K; Moriyama, T; Torisu, T; Nagai, E; Morisaki, T; Kitazono, T; Oda, Y; Nakamura, M

    CLINICAL AND TRANSLATIONAL MEDICINE   13 ( 1 )   e1181   2023.1   ISSN:2001-1326

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  • ERAP2 is a novel target involved in autophagy and activation of pancreatic stellate cells via UPR signaling pathway (vol 22, pg 9, 2022)

    Guan, W; Nakata, K; Sagara, A; Iwamoto, C; Endo, S; Matsuda, R; Matsumoto, S; Ikenaga, N; Shindo, K; Moriyama, T; Onishi, H; Ohuchida, K; Oda, Y; Nakamura, M

    PANCREATOLOGY   22 ( 7 )   1059 - 1059   2022.11   ISSN:1424-3903 eISSN:1424-3911

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    Language:English   Publisher:Pancreatology  

    Figures in this paper contained western blots where the same membrane was probed repeatedly by the indicated antibodies, occasionally resulting in similar band shapes among the individual panels. Moreover, in Figure 5, results from the same membrane were presented in two columns with the panels for the α-SMA and β-actin blots shown twice for easier comparison. We apologize for any misunderstanding this may have caused.

    DOI: 10.1016/j.pan.2022.08.013

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  • Subtypes in pancreatic ductal adenocarcinoma based on niche factor dependency show distinct drug treatment responses

    Shinkawa, T; Ohuchida, K; Mochida, Y; Sakihama, K; Iwamoto, C; Abe, T; Ideno, N; Mizuuchi, Y; Shindo, K; Ikenaga, N; Moriyama, T; Nakata, K; Oda, Y; Nakamura, M

    JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH   41 ( 1 )   89   2022.3   ISSN:0392-9078 eISSN:1756-9966

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    Language:English   Publisher:Journal of Experimental and Clinical Cancer Research  

    Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma in which microenvironmental (niche) factors promote PDAC progression. In mouse models, reduction of the stroma increased the proportion of poorly differentiated PDAC with a worse prognosis. Here, we aimed to clarify the effects of stroma on PDAC that may define the PDAC phenotype and induce distinct therapeutic responses. Methods: The molecular features of PDAC based on differentiation grade were clarified by genome and transcriptome analysis using PDAC organoids (PDOs). We identified the dependency on niche factors that might regulate the differentiation grade. A three-dimensional co-culture model with cancer-associated fibroblasts (CAFs) was generated to determine whether CAFs provide niche factors essential for differentiated PDAC. PDOs were subtyped based on niche factor dependency, and the therapeutic responses for each subtype were compared. Results: The expression profiles of PDOs differed depending on the differentiation grade. Consistent with the distinct profiles, well differentiated types showed high niche dependency, while poorly differentiated types showed low niche dependency. The three-dimensional co-culture model revealed that well differentiated PDOs were strongly dependent on CAFs for growth, and moderately differentiated PDOs showed plasticity to change morphology depending on CAFs. Differentiated PDOs upregulated the expression of mevalonate pathway-related genes correlated with the niche dependency and were more sensitive to simvastatin than poorly differentiated PDOs. Conclusions: Our findings suggest that CAFs maintain the differentiated PDAC phenotype through secreting niche factors and induce distinct drug responses. These results may lead to the development of novel subtype-based therapeutic strategies.

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  • ERAP2 is a novel target involved in autophagy and activation of pancreatic stellate cells via UPR signaling pathway

    Guan, W; Nakata, K; Sagara, A; Iwamoto, C; Endo, S; Matsuda, R; Matsumoto, S; Ikenaga, N; Shindo, K; Moriyama, T; Onishi, H; Ohuchida, K; Oda, Y; Nakamura, M

    PANCREATOLOGY   22 ( 1 )   9 - 19   2022.1   ISSN:1424-3903 eISSN:1424-3911

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    Language:English   Publisher:Pancreatology  

    Background/objectives: Pancreatic ductal adenocarcinoma (PDAC) is characterized by excessive desmoplasia and autophagy-dependent tumorigenic growth. Pancreatic stellate cells (PSCs) as a predominant stromal cell type play a critical role in PDAC biology. We have previously reported that autophagy facilitates PSC activation, however, the mechanism remains unknown. We investigated the mechanism of autophagy in PSC activation. Methods: We compared gene expression profiles between patient-derived PSCs from pancreatic cancer and chronic pancreatitis using a microarray. The stromal expression of target gene in specimen of PDAC patients (n = 63) was analyzed. The effect of target gene on autophagy and activation of PSCs was investigated by small interfering RNAs transfection, and the relationship between autophagy and ER stress was investigated. We analyzed the growth and fibrosis of xenografted tumor by orthotopic models. Results: In analysis of gene expression microarray, endoplasmic reticulum aminopeptidase 2 (ERAP2) upregulated in cancer-associated PSCs was identified as the target gene. High stromal ERAP2 expression is associated with a poor prognosis of PDAC patients. Knockdown of ERAP2 inhibited unfolded protein response mediated autophagy, and led to inactivation of PSCs, thereby attenuating tumor-stromal interactions by inhibiting production of IL-6 and fibronectin. In vivo, the promoting effect of PSCs on xenografted tumor growth and fibrosis was inhibited by ERAP2 knockdown. Conclusions: Our findings demonstrate a novel mechanism of PSCs activation regulated by autophagy. ERAP2 as a promising therapeutic target may provide a novel strategy for the treatment of PDAC.

    DOI: 10.1016/j.pan.2021.09.012

    Web of Science

    Scopus

    PubMed

  • Bone marrow-derived macrophages converted into cancer-associated fibroblast-like cells promote pancreatic cancer progression. Reviewed International journal

    C Iwamoto, K Ohuchida, T Shinkawa, S Okuda, Y Otsubo, T Okumura, A Sagara, K Koikawa, Y Ando, K Shindo, N Ikenaga, K Nakata, T Moriyama, Y Miyasaka, T Ohtsuka, M Eto, K Akashi, M Nakamura.

    Cancer Letters   2021.8

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  • Postmortem interval estimation using the animal model of postmortem gas volume changes. Reviewed International journal

    C Iwamoto, K Ohuchida, M Okumura, Y Usumoto, J Kishimoto, M Murata, N Ikeda, M Hashizume.

    Legal Medicine   2018.5

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  • The BALB/c-specific polymorphic SIRPA enhances its affinity for human CD47, inhibiting phagocytosis against human cells to promote xenogeneic engraftment. Reviewed International journal

    C Iwamoto, K Takenaka, S Urata, T Yamauchi, T Shima, T Kuriyama, S Daitoku, Y Saito, T Miyamoto, H Iwasaki, I Kitabayashi, K Itoh, J Kishimoto, D Kohda, T Matozaki, and K Akashi.

    Exp Hematologist   2014.3

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Presentations

  • MHC提示ペプチド変異を標的とした膵癌治療のパラダイムシフト:早期発見から治療まで

    岩本 千佳, 大内田研宙, 堤親範, 小山虹輝, 久保顕博, 阿部俊也, 渡邉雄介, 井手野昇, 池永直樹, 仲田興平, 中村雅史

    第45回癌免疫外科研究会  2024.5 

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    Event date: 2024.5

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:ワークピア横浜   Country:Japan  

  • MHC class I mutation in CTCs is an indicator of early detection of PDAC and at the same time a possible target of anti-cancer immune reaction. International conference

    Chika Iwamoto, Kenoki Ohuchida, Chikanori Tsutsumi, Koji Shindo, Koki Oyama, Masataka Hayashi, Akihiro Kubo, Nobuhiro Higashijima, Toshiya Abe, Yusuke Watanabe, Noboru Ideno, Naoki Ikenaga, Kohei Nakata, Masafumi Nakamura

    54th American Pancreatic Association 2023 Annual Meeting  2023.11 

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    Event date: 2023.11

    Language:English  

    Country:United States  

  • CTCsにおけるMHCクラスI変異はPDACの早期発見の指標であると同時に抗腫瘍免疫応答の標的となりうる

    @岩本 千佳,@大内田 研宙,#堤 親範,@進藤 幸治,#小山 虹輝,@林 昌孝,#久保 顕博,#東島亘宏,@阿部 俊也,@渡邉 雄介,@井手野 昇,@池永直樹,@仲田興平,@中村雅史

    第50回日本膵切研究会  2023.8 

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    Event date: 2023.8

    Language:Japanese  

    Country:Japan  

  • 造血幹細胞由来CAF subsetが腫瘍内heterogeneityを高度化する

    岩本千佳, 大内田研宙, 新川智彦, 相良亜希子, 奥田翔, 小山虹輝, 進藤幸治, 池永直樹, 仲田興平, 森山大樹, 中村雅史.

    第52回日本膵臓学会大会  2021.9 

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    Event date: 2021.9

    Language:Japanese  

    Venue:グランドニッコー東京台場   Country:Japan  

  • Development of PDX models with functional human blood and immune systems in pancreatic cancer.

    2021.7 

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    Event date: 2021.7

    Language:Japanese  

    Country:Japan  

  • HSCs transformed into CAFs in the tumor microenvironment induce the invasion of pancreatic cancer.

    2020.12 

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    Event date: 2020.12

    Language:Japanese  

    Country:Japan  

  • Human macrophages-derived CAF-like cells lead the invasion of pancreatic cancer. International conference

    C Iwamoto, K Ohuchida, T Shinkawa, Y Ohtsubo, K Shindo, T Moriyama, K Nakata, T Ohtsuka, M Nakamura.

    14th World Congress of the International Hepato-Pancreato-Biliary Association (IHPBA)  2020.11 

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    Event date: 2020.11

    Language:English  

    Country:Australia  

  • BM-derived Cells Destruct Basemen Membrane and Induce Local Invasion of Pancreatic Cancer. International conference

    C Iwamoto, K Ohuchida, Y Ando, T Shinkawa, Y Ohtsubo, K Shindo, T Moriyama, K Nakata, K Miyawaki, T Ohtsuka, K Akashi, M Eto, M Nakamura.

    50th Annual Meeting of the American Pancreatic Association  2019.11 

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    Event date: 2019.11

    Language:English  

    Country:United States  

  • BM-derived cells multilineage hematopoietic cells that constitute tumor microenvironment lead invasion of pancreatic cancer.

    2019.9 

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    Event date: 2019.9

    Language:Japanese  

    Country:Japan  

  • 膵臓に誘導され膵癌微小環境を構成する骨髄由来細胞が膵癌浸潤を制御する

    岩本千佳, 大内田研宙, 武居晋, 進藤幸治, 宮脇恒太, 赤司浩一, 橋爪誠, 江藤正俊 中村雅史.

    第74回日本消化器外科学会総会  2019.7 

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    Event date: 2019.7

    Language:Japanese  

    Venue:グランドプリンスホテル新高輪   Country:Japan  

  • Accumulation and integration of various medical images derived from KPC mice and resected human pancreases. International conference

    C Iwamoto, K Ohuchida, M Hashizume.

    2019.3 

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    Event date: 2019.3

    Language:English  

    Country:Japan  

  • BM-derived cells recruited to the pancreas compose the tumor microenvironment and promote invasion of pancreatic cancer.

    2018.9 

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    Event date: 2018.9

    Language:Japanese  

    Country:Japan  

  • BM-derived cells recruited to the pancreas constitute the tumor microenvironment and promote invasion of pancreatic cancer. International conference

    C Iwamoto, K Ohuchida, T Okumura, K Koikawa, S Takesue, H Nakayama, S Endo, S Kibe, Y Ando, K Miyawaki, M Murata, K Akashi, M Nakamura, M Hashizume.

    49th Digestive Disease Week  2018.6 

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    Event date: 2018.6

    Language:English  

    Country:United States  

  • BM-derived Cells Differentiated into Multilineage Hematopoietic Cells Regulate Invasion and Proliferation of Pancreatic Cancer. International conference

    C Iwamoto, K Ohuchida, T Okumura, K Koikawa, S Takesue, H Nakayama, S Endo, S Kibe, Y Ando, K Shindo, K Nakata, K Miyawaki, M Murata, K Akashi, M Nakamura, M Hashizume.

    Pancreas  2018.4 

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    Event date: 2018.4

    Language:English  

    Country:United States  

  • BM-derived cells are involved in the tumor microenvironment and promote invasion of pancreatic cancer. International conference

    C Iwamoto, K Ohuchida, T Okumura, K Koikawa, S Takesue, H Nakayama, S Endo, S Kibe, Y Ando, T Abe, K Miyawaki, M Murata, K Akashi, M Nakamura, M Hashizume.

    48th Annual Meeting of the American Pancreatic Association  2017.11 

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    Event date: 2017.11

    Language:English  

    Country:United States  

  • 膵癌(基礎) 膵癌治療におけるオートファジー研究 10年先の予後改善を目指して

    仲田 興平, 鐘 坪杉, 小山 虹輝, 相良 亜紀子, 遠藤 翔, 阿部 俊也, 渡邉 雄介, 井手野 昇, 池永 直樹, 岩本 千佳, 田村 公二, 藤本 崇聡, 大内田 研宙, 中村 雅史

    膵臓  2024.7  (一社)日本膵臓学会

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  • 膵癌細胞のAutophagyを標的とした新たな抗腫瘍免疫増強メカニズムの解明

    小山 虹輝, 仲田 興平, 林 昌孝, 伊達 聡美, 持田 郁己, 岩本 千佳, 池永 直樹, 大内田 研宙, 中村 雅史

    膵臓  2023.7  (一社)日本膵臓学会

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  • 膵腫瘍内の歯周病菌Fusobacterium nucleatumはCXCL1-CXCR2シグナルを介して膵癌の進展を促進する

    林 昌孝, 池永 直樹, 仲田 興平, 岩本 千佳, 伊達 聡美, 小山 虹輝, 東島 亘宏, 久保 顕博, 阿部 俊也, 井手野 昇, 中村 雅史

    日本胆膵病態・生理研究会プログラム・抄録集  2023.6  日本胆膵病態・生理研究会

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  • 術前化学療法施行後の膵癌組織内グラム陰性菌が癌微小環境に与える影響の解明

    久保 顕博, 岩本 千佳, 仲田 興平, 小山 虹輝, 堤 親範, 島田 有貴, 山田 裕, 伊達 聡美, 東島 亘宏, 廣高 健斗, 松吉 隆仁, 阿部 俊也, 渡邉 雄介, 井手野 昇, 池永 直樹, 大内田 研宙, 小田 義直, 中村 雅史

    膵臓  2024.7  (一社)日本膵臓学会

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  • 膵疾患と腸内細菌・シンバイオティクス 膵がんは腸内細菌を介して免疫抑制性微小環境を構築する

    池永 直樹, 林 昌孝, 松吉 隆仁, 小山 虹輝, 阿部 俊也, 岩本 千佳, 大内田 研宙, 仲田 興平, 中村 雅史

    膵臓  2024.7  (一社)日本膵臓学会

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  • 膵腫瘍内の歯周病菌Fusobacterium nucleatumはCXCL1-CXCR2シグナルを介して膵癌の進展を促進する

    林 昌孝, 池永 直樹, 仲田 興平, 岩本 千佳, 伊達 聡美, 小山 虹輝, 東島 亘宏, 久保 顕博, 阿部 俊也, 井手野 昇, 中村 雅史

    日本胆膵病態・生理研究会プログラム・抄録集  2023.6  日本胆膵病態・生理研究会

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  • 膵癌細胞のAutophagyを標的とした新たな抗腫瘍免疫増強メカニズムの解明

    小山 虹輝, 仲田 興平, 林 昌孝, 伊達 聡美, 持田 郁己, 岩本 千佳, 池永 直樹, 大内田 研宙, 中村 雅史

    膵臓  2023.7  (一社)日本膵臓学会

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  • ERAP2は膵癌進展に関わるオートファジー制御遺伝子である

    伊達 聡美, 仲田 興平, 林 昌孝, 小山 虹輝, 岩本 千佳, 池永 直樹, 大内田 研宙, 中村 雅史

    膵臓  2023.7  (一社)日本膵臓学会

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  • CTCsにおけるMHCクラスI変異は膵癌の早期発見の指標となりうる

    岩本 千佳, 大内田 研宙, 堤 親範, 小山 虹輝, 久保 顕博, 東島 亘宏, 阿部 俊也, 渡邉 雄介, 井手野 昇, 池永 直樹, 仲田 興平, 中村 雅史

    膵臓  2024.7  (一社)日本膵臓学会

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  • ERAP2は膵癌進展に関わるオートファジー制御遺伝子である

    伊達 聡美, 仲田 興平, 林 昌孝, 小山 虹輝, 岩本 千佳, 池永 直樹, 大内田 研宙, 中村 雅史

    膵臓  2023.7  (一社)日本膵臓学会

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  • パブリックデータを利用した膵癌癌関連線維芽細胞内の遺伝子変化の検討

    東島 亘宏, 仲田 興平, 伊達 聡美, 久保 顕博, 小山 虹輝, 池永 直樹, 岩本 千佳, 大内田 研宙, 中村 雅史

    膵臓  2024.7  (一社)日本膵臓学会

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MISC

  • 【膵腫瘍の分子多様性~病態の不均一性を紐解く~】家族性からみた膵癌の分子多様性

    阿部 俊也, 仲田 興平, 岩本 千佳, 渡邉 雄介, 井手野 昇, 池永 直樹, 中村 雅史

    胆と膵   45 ( 7 )   721 - 724   2024.7   ISSN:0388-9408

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    Language:Japanese   Publisher:医学図書出版(株)  

    家族性膵癌とは膵癌に罹患した2人以上の第1度近親者がいる家系に発症する膵癌,と定義され,膵癌全体の約10%を占める。網羅的な遺伝子解析により,膵癌発症リスクが濃厚な膵癌家族歴と相関することや,BRCA1/2などのDNA相同組み換え修復に関連する生殖細胞遺伝子バリアントが家族性膵癌の発症に関連することが報告された。一方で家族性膵癌の中で約80%の患者では特定の病的遺伝子が同定されておらず,現在も研究が進められている。個別化医療の実現や膵癌の早期発見のための膵癌高リスク個人のサーベイランスを確立するために,家族性膵癌の多様性のさらなる解明が今後の課題である。(著者抄録)

  • 【腸内細菌叢と癌治療】腸内細菌と膵がん治療

    池永 直樹, 林 昌孝, 松吉 隆仁, 岩本 千佳, 仲田 興平, 大内田 研宙, 中村 雅史

    癌と化学療法   51 ( 6 )   603 - 607   2024.6   ISSN:0385-0684

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    Language:Japanese   Publisher:(株)癌と化学療法社  

    歯周病と膵がん発生の相関は以前より示唆されていた。ゲノム解析の技術進歩により膵がん患者の腸や腫瘍内に膵がん特異的な細菌叢が形成され,膵がんの進展を修飾することが明らかになってきた。腸内細菌の乱れ(ディスバイオーシス)は膵がんに対する腫瘍免疫を抑制し,がんの進展を助長している。そのためプロバイオティクスや菌叢移植でディスバイオーシスを是正し,がんに対する免疫チェックポイント阻害剤を賦活する治療が試みられている。また,膵がん細胞とのクロストークから免疫抑制性微小環境を構築している特定の腫瘍内細菌も明らかにされている。将来的には膵がん腫瘍内の菌叢分布を解析し,解析結果に応じた個別化治療も検討されると思われる。オミックス技術の革新で,より詳細な腸内細菌の機能が明らかとなり,有効な膵がん治療が開発されることを期待する。(著者抄録)

  • 【膵癌基礎研究の最前線RELOADED】Humanizedマウスを用いた膵癌PDXモデルの作製と膵癌微小環境の解析

    岩本 千佳, 大内田 研宙, 池永 直樹, 仲田 興平, 中村 雅史

    胆と膵   45 ( 2 )   111 - 115   2024.2   ISSN:0388-9408

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    Language:Japanese   Publisher:医学図書出版(株)  

    膵癌をはじめとする悪性腫瘍の病態理解や新規治療法の開発には,マウスモデルは必要不可欠であり,その中でも異種移植モデルは欠かせないプラットフォームである。これまでに培養細胞を移植するcell line-derived xenograft(CDX)モデルや患者由来切除組織片を移植するpatient-derived xenograft(PDX)モデルが開発されてきた。これにより,腫瘍の発生・増大,遺伝子発現解析,バイオマーカー探索,薬剤の有効性評価など,癌研究において新たな知見が見出されており,適切な解析系を選択することが重要であると言える。近年,悪性腫瘍に対する第4の治療法として脚光を浴びている癌免疫療法研究の解析ツールとして,膵癌のhumanized PDXマウスモデルを開発した。従来のマウスモデルと異なり,マウス内にヒト造血・免疫系細胞が再構築されているため,癌免疫療法の解析に必要な免疫応答の評価が可能なモデルとして期待できる。しかし,膵癌humanized PDXモデルにおいて生着した免疫細胞の割合がヒト生体内でみられる割合とは異なることやマウスモデルの安定的な供給には,さらなる改良が必要である。(著者抄録)

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Professional Memberships

  • Japanese Cancer Association

  • Japan Pancreas Society

  • The Japanese Society of Hematology

  • The Japanese Society of Gastroenterological Surgery

Research Projects

  • 腫瘍浸潤白血球に高度に濃縮されるCHIPの膵癌微小環境に対する潜在的な影響の解明

    Grant number:24K11869  2024 - 2026

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    岩本 千佳, 中村 雅史, 進藤 幸治, 藤本 崇聡, 新川 智彦

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    Authorship:Principal investigator  Grant type:Scientific research funding

    CHIPは血液腫瘍や炎症性疾患など幅広い病態と関連付けられており、CHIP変異は検出される遺伝子や細胞により臨床的意義が異なる。固形腫瘍におけるCHIPの発生率は癌腫によって異なることが言われ始めているが、固形腫瘍におけるCHIPの影響うは現在のところ殆ど解明されていない。そこで我々は、膵癌のCHIPを詳細に解明することで、病態形成や腫瘍免疫微小環境に新たな知見をもたらすだけでなく、がん免疫療法の効果増大や持続性の改良を目指す。

    CiNii Research

  • 膵癌に対する抗腫瘍免疫抑制性環境の改変を目指したCAR-T療法の開発

    Grant number:22H00480  2022.4 - 2025.3

    科学研究費助成事業  基盤研究(A)

    中村 雅史, 岩本 千佳, 大内田 研宙, 竹中 克斗, 村田 正治, 仲田 興平, 森崎 隆

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    Grant type:Scientific research funding

    膵癌が治療抵抗性である要因として腫瘍免疫抑制的な環境があるが、癌間質細胞(CAF)が原因の一つであると考えられている。また、CAFのheterogeneityの解明が進み、膵癌でも複数の機能的CAFクラスターの存在が明らかにされてきたが、腫瘍免疫抑制の要因となる機能的CAFクラスターは同定されていない。本研究では抗腫瘍免疫抑制的な環境を構築する特定のCAFクラスターを同定し、そのようなCAFクラスターを標的とするキメラ抗原受容体T細胞(CAR-T)療法を開発する。

    CiNii Research

  • 膵癌におけるマクロファージ免疫チェックポイントdual mechanismの解明

    Grant number:21K08779  2021 - 2023

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    岩本 千佳, 大内田 研宙

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    Authorship:Principal investigator  Grant type:Scientific research funding

    膵癌における有効なマクロファージ免疫チェックポイント分子やその作用機序は殆ど解明されていない。そこで"Don't eat me" signal と"Eat me" signalのdual mechnismをもつマクロファージ免疫チェックポイントによる膵癌微小免疫環境の維持機構を解明する。腫瘍内マクロファージを中心とした免疫監視機構の制御により、抗腫瘍効果を回復させる新規免疫療法の確立を目指す。

    CiNii Research

  • Construction of drug discovery library using PDX-3D method and discovery of novel therapeutic agents for pancreatic cancer

    Grant number:20H03754  2020.4 - 2023.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    MIZUMOTO Kazuhiro

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    Grant type:Scientific research funding

    We developed the original drug screening using fat-droplet staining in pancreatic stellate cells to develop new stromal-targeted therapeutics in pancreatic cancer. The identified candidate drugs inhibited cancer-stromal interactions and showed marked tumor shrinkage when combined with immune checkpoint inhibitors, suggesting that they could enhance tumor immunity.

    CiNii Research

  • Gene expression mapping of esophageal cancer microenvironment by spatial transcriptomics

    Grant number:20K09080  2020.4 - 2023.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    INOUE Shigetaka

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    Grant type:Scientific research funding

    In recent years, single-cell analysis has attracted attention for elucidating the mechanisms of cancer invasion and metastasis. we initiated this study using Visium, a new technology, to create a gene expression map consistent with conventional pathomorphology and to elucidate the tumor microenvironment. Data from esophageal cancer samples show that chemotherapy reduces the immunosuppressive capacity of regulatory T cells, cytotoxic T cells evade exhaustion, and helper T cells are induced to become more memory-intensive and prevent exhaustion. These results suggest that chemotherapy may enhance anti-tumor immunity by immune cells in esophageal cancer.

    CiNii Research

  • 膵癌進展を促す骨髄由来細胞による癌細胞clonalityの選択機序解明とその制御

    Grant number:18K16366  2018 - 2020

    日本学術振興会  科学研究費助成事業  若手研究

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    Authorship:Principal investigator  Grant type:Scientific research funding

  • 膵癌の発癌・進展に関わる骨髄由来leading cellの同定と新規治療法の開発

    Grant number:16K19937  2016 - 2017

    科学研究費助成事業  若手研究(B)

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    Authorship:Principal investigator  Grant type:Scientific research funding

  • 膵癌浸潤/転移を導く骨髄由来leading cellの同定とその制御法の開発

    Grant number:15H06480  2015 - 2016

    日本学術振興会  科学研究費助成事業  研究活動スタート支援

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    Authorship:Principal investigator  Grant type:Scientific research funding

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