Development of tumor-host integrative therapies to overcome the refractory nature of uterine serous carcinoma

• Project/Area Number: 18K09287
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Iwate Medical University
• Principal Investigator: B Tsukasa 岩手医科大学, 医学部, 教授 (60508240)
• Co-Investigator(Kenkyū-buntansha): 村上 隆介 京都大学, 医学研究科, 特定病院助教 (40782363) ; 万代 昌紀 京都大学, 医学研究科, 教授 (80283597) ; Brown John 京都大学, 医学研究科, 講師 (90583188)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 子宮体癌 / 漿液性癌 / 治療抵抗性 / 動物モデル / マウスモデル / MDSC / プラチナ耐性 / 子宮体部漿液性癌 / 化学療法抵抗性 / 抗腫瘍免疫逃避

Outline of Final Research Achievements

Serous uterine carcinoma (SEC), which accounts for 10% of all uterine cancers, is highly metastatic and often resistant to treatment. In this study, through comprehensive genetic analysis of SEC, we found that Myc activity regulates the malignant nature of SEC and its downstream factors may be potential therapeutic targets. Furthermore, since the anti-tumor immune evasion mechanism was enhanced in SEC in human clinical specimens, we also focused on the anti-tumor immune evasion mechanism and created a mouse model of SEC under normo-immune conditions. Using this model, we searched for anti-tumor immune evasion mechanisms between cancer and host, and found that CCL7 secretion from tumor cells was an important factor as a transduction signal. We submitted these results as an original research article and have begun to expand on our previous findings and search for therapies that act on cancer-host signaling.

Academic Significance and Societal Importance of the Research Achievements

現在までに有効な治療法の無いSECについてはドライバー遺伝子や治療候補薬剤を同定したという報告もあるが、再現性を示す報告や免疫健常生体内での有効性を示す報告は見られない。我々はこれまで国内外の研究者の協力を得て多コホート・多細胞株での検討を重ねmyc/STAT1がSECの多様な治療抵抗性を司り、予後不良因子となることを明らかにしてきた。これまでの課題を基にSECの免疫健常マウスモデルを作成し、対照モデルとの比較でSECの抗腫瘍免疫逃避機構の一端を明らかにした。この成果は今後のSEC研究への発展に留まらず、女性の健康を蝕む他癌腫にも応用できる可能性が高く、本研究の学術的独自性は高いと考えられる。

Research Products

• [Journal Article] Immunosuppressive tumor microenvironment in Uterine Serous Carcinoma via CCL7 signal with myeloid-derived suppressor cells. (2022)
  • Author(s): Mise Y, Hamanishi J, Daikoku T, Takamatsu S, Miyamoto T, Taki M, Yamanoi K, Yamaguchi K, Ukita M, Horikawa N, Abiko K, Murakami R, Furutake Y, Hosoe Y, Terakawa J, Kagabu M, Sugai T, Osakabe M, Fujiwara H, Matsumura N, Mandai M, Baba T.
  • Journal Title: Carcinogenesis Volume: na Issue: 7 Pages: 647-658
  • DOI: 10.1093/carcin/bgac032
  • Peer Reviewed / Open Access
• [Journal Article] B7-H3 Suppresses Antitumor Immunity via the CCL2-CCR2-M2 Macrophage Axis and Contributes to Ovarian Cancer Progression (2022)
  • Author(s): Miyamoto T, Murakami R, Hamanishi J, Tanigaki K, Hosoe Y, Mise N, Takamatsu S, Mise Y, Ukita M, Taki M, Yamanoi K, Horikawa N, Abiko K, Yamaguchi K, Baba T, Matsumura N, Mandai M.
  • Journal Title: Cancer Immunol Res . Volume: 10 Issue: 1 Pages: 56-69
  • DOI: 10.1158/2326-6066.cir-21-0407
  • Peer Reviewed / Open Access
• [Journal Article] PDK2 leads to cisplatin resistance through suppression of mitochondrial function in ovarian clear cell carcinoma (2021)
  • Author(s): Kitamura S, Yamaguchi K, Murakami R, Furutake Y, Higasa K, Abiko K, Hamanishi J, Baba T, Matsumura N, Mandai M.
  • Journal Title: Cancer Sci. Volume: 112 Issue: 11 Pages: 4627-4640
  • DOI: 10.1111/cas.15125
  • Peer Reviewed / Open Access
• [Journal Article] Combination of gene set signatures correlates with response to nivolumab in platinum-resistant ovarian cancer (2021)
  • Author(s): Murakami R, Hamanishi J, Brown JB, Abiko K, Yamanoi K, Taki M, Hosoe Y, Yamaguchi K, Baba T, Matsumura N, Konishi I, Mandai M.
  • Journal Title: Sci Rep . Volume: 11 Issue: 1 Pages: 11427-11427
  • DOI: 10.1038/s41598-021-91012-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tumor Immune Microenvironment during Epithelial-Mesenchymal Transition. (2021)
  • Author(s): Taki M, Abiko K, Ukita M, Murakami R, Yamanoi K, Yamaguchi K, Hamanishi J, Baba T, Matsumura N, Mandai M.
  • Journal Title: Clin Cancer Res Volume: - Issue: 17 Pages: 4459-4459
  • DOI: 10.1158/1078-0432.ccr-20-4459
  • Peer Reviewed / Open Access
• [Journal Article] Microcystic, Elongated and Fragmented Pattern Invasion Can Adversely Influence Preoperative Staging for Low-grade Endometrial Carcinoma (2021)
  • Author(s): Kuwahara R, Kido A, Yajima R, Nishio N, Nakao K, Kurata Y, Tanaka S, Minamiguchi S, Baba T, Mandai M, Togashi K.
  • Journal Title: Magnetic Resonance in Medical Sciences Volume: 20 Issue: 1 Pages: 20-27
  • DOI: 10.2463/mrms.mp.2019-0153
  • NAID: 130007993618
  • ISSN: 1347-3182, 1880-2206
  • Peer Reviewed / Open Access
• [Journal Article] Clinical relevance of endometrial polyps diagnosed by hysteroscopy in 613 infertile women: a retrospective, single-center, cohort study (2020)
  • Author(s): Onoue Hiroki、Baba Tsukasa、Koiwa Kanako、Kon Michiko、Ikeda Maki、Kumagai Jin
  • Journal Title: Obstetrics & Gynecology International Journal Volume: 11 Issue: 3 Pages: 137-141
  • DOI: 10.15406/ogij.2020.11.00500
  • Peer Reviewed / Open Access
• [Journal Article] Treatment outcomes of intrauterine insemination and pregnancy prognosis factors: a retrospective single-center cohort study (2020)
  • Author(s): Onoue Hiroki、Baba Tsukasa、Koiwa Kanako、Kon Michiko、Tsuchiya Shigeichiro、Satoh Chie
  • Journal Title: International Journal of Family & Community Medicine Volume: 4 Issue: 3 Pages: 78-81
  • DOI: 10.15406/ijfcm.2020.04.00189
  • Peer Reviewed / Open Access
• [Journal Article] UGT1A1 polymorphism has a prognostic effect in patients with stage IB or II uterine cervical cancer and one or no metastatic pelvic nodes receiving irinotecan chemotherapy: a retrospective study (2020)
  • Author(s): Matsuoka Hideki、Murakami Ryusuke、Abiko Kaoru、Yamaguchi Ken、Horie Akihito、Hamanishi Junzo、Baba Tsukasa、Mandai Masaki
  • Journal Title: BMC Cancer Volume: 20 Issue: 1 Pages: 729-729
  • DOI: 10.1186/s12885-020-07225-1
  • Peer Reviewed / Open Access
• [Journal Article] Targeting Dormant Ovarian Cancer Cells In Vitro and in an In Vivo Mouse Model of Platinum Resistance (2020)
  • Author(s): Huang Zhiqing、Kondoh Eiji、Visco Zachary R.、Baba Tsukasa、Matsumura Noriomi、Dolan Emma、Whitaker Regina S.、Konishi Ikuo、Fujii Shingo、Berchuck Andrew、Murphy Susan K.
  • Journal Title: Molecular Cancer Therapeutics Volume: 20 Issue: 1 Pages: 85-95
  • DOI: 10.1158/1535-7163.mct-20-0119
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genome?wide analysis of microRNA to evaluate prognostic markers in isolated cancer glands and surrounding stroma in high?grade serous ovarian carcinoma (2020)
  • Author(s): Sato Chie、Osakabe Mitsumasa、Nagasawa Takayuki、Suzuki Hiromu?、Itamochi Hiroaki、Baba Tsukasa、Sugai Tamotsu
  • Journal Title: Oncology Letters Volume: 20 Issue: 6 Pages: 1-1
  • DOI: 10.3892/ol.2020.12198
  • Peer Reviewed / Open Access
• [Journal Article] The efficacy of a third-generation oncolytic herpes simplex viral therapy for an HPV-related uterine cervical cancer model (2020)
  • Author(s): Kagabu Masahiro、Yoshino Naoto、Saito Tatsunori、Miura Yuki、Takeshita Ryosuke、Murakami Kazuyuki、Kawamura Hideki、Baba Tsukasa、Sugiyama Toru
  • Journal Title: International Journal of Clinical Oncology Volume: 26 Issue: 3 Pages: 591-597
  • DOI: 10.1007/s10147-020-01823-6
  • Peer Reviewed / Open Access
• [Journal Article] Anti-VEGF therapy resistance in ovarian cancer is caused by GM-CSF-induced myeloid-derived suppressor cell recruitment. (2020)
  • Author(s): Horikawa N, Abiko K, Matsumura N, Baba T, Hamanishi J, Yamaguchi K, Murakami R, Taki M, Ukita M, Hosoe Y, Koshiyama M, Konishi I, Mandai M.
  • Journal Title: Br J Cancer. Volume: 122(1) Issue: 6 Pages: 778-788
  • DOI: 10.1038/s41416-019-0725-x
  • Peer Reviewed / Open Access
• [Journal Article] Hysteroscopic morphological pattern reflects histological grade of endometrial cancer. (2019)
  • Author(s): Miyamoto T, Abiko K, Murakami R, Furutake Y, Baba T, Horie A, Hamanishi J, Mandai M.
  • Journal Title: J Obstet Gynaecol Res. Volume: 45(8) Issue: 8 Pages: 1479-1487
  • DOI: 10.1111/jog.13998
  • Peer Reviewed / Open Access
• [Journal Article] Tumor characteristics and outcome of uterine carcinosarcoma in women aged 80 years. (2019)
  • Author(s): Matsuo K, Ross MS, Yunokawa M, Shida M,Mikami M,et al.
  • Journal Title: Surg Oncol Volume: 29 Pages: 25-32
  • DOI: 10.1016/j.suronc.2019.02.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phosphorylation of STAT1 Serine 727 Enhances Platinum Resistance in Uterine Serous Carcinoma. (2019)
  • Author(s): Zeng X, Baba T, Hamanishi J, Matsumura N, Budiman K, Mise Y, Abiko K, Yamaguchi K, Horikawa N, Huntsman DG, Mulati K, Kitamura S, Taki M, Murakami R, Hosoe Y, Mandai M.
  • Journal Title: Int J Cancer. Volume: 145(6) Issue: 6 Pages: 1635-1647
  • DOI: 10.1002/ijc.32501
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Acquisition of a side population fraction augments malignant phenotype in ovarian cancer. (2019)
  • Author(s): Yamanoi K, Baba T, Abiko K, Hamanishi J, Yamaguchi K, Murakami R, Taki M, Hosoe Y, Murphy SK, Konishi I, Mandai M, Matsumura N.
  • Journal Title: Sci Rep. Volume: 9(1) Issue: 1 Pages: 14215-14215
  • DOI: 10.1038/s41598-019-50794-w
  • NAID: 120006822513
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immunotherapy for Uterine Cervical Cancer. (2019)
  • Author(s): Kagabu M, Nagasawa T, Fukagawa D, Tomabechi H, Sato S, Shoji T, Baba T. Immunotherapy for Uterine Cervical Cancer.
  • Journal Title: Healthcare (Basel). Volume: 7(3) Issue: 3 Pages: 108-108
  • DOI: 10.3390/healthcare7030108
  • Peer Reviewed / Open Access
• [Journal Article] Early feasibility surveillance of gynecologic robotic‐assisted surgeries in Japan (2019)
  • Author(s): Baba Tsukasa、Mandai Masaki、Nishi Hirotaka、Nishii Osamu、Kitawaki Jo、Sawada Morio、Isaka Keiichi、Fujii Tomoyuki
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 45 Issue: 4 Pages: 787-793
  • DOI: 10.1111/jog.13923
  • Peer Reviewed
• [Journal Article] 漿液性癌のゲノム解析 (2018)
  • Author(s): 馬場 長
  • Journal Title: 婦人科がん（第2版） ―最新の研究動向― Volume: 1138号 Pages: 390-396
• [Journal Article] 【がん免疫療法の新展開-「知らない」ではすまない今のトレンド】 今日のがん免疫療法をわかりやすく理解するために (2018)
  • Author(s): 万代昌紀, 濱西 潤三, 安彦 郁, 馬場 長
  • Journal Title: 臨床婦人科産科 Volume: 72巻6号 Pages: 518-523
• [Journal Article] 卵巣がんの免疫逃避のメカニズム (2018)
  • Author(s): 馬場長、滝真奈
  • Journal Title: 医学のあゆみ Volume: 269巻4号 Pages: 302-304
• [Journal Article] VISTA expressed in tumour cells regulates T cell function (2018)
  • Author(s): Mulati Kumuluzi、Hamanishi Junzo、Matsumura Noriomi、Chamoto Kenji、Mise Nathan、Abiko Kaoru、Baba Tsukasa、Yamaguchi Ken、Horikawa Naoki、Murakami Ryusuke、Taki Mana、Budiman Kharma、Zeng Xiang、Hosoe Yuko、Azuma Miyuki、Konishi Ikuo、Mandai Masaki
  • Journal Title: British Journal of Cancer Volume: 120 Issue: 1 Pages: 115-127
  • DOI: 10.1038/s41416-018-0313-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characterizing sarcoma dominance pattern in uterine carcinosarcoma: Homologous versus heterologous element (2018)
  • Author(s): Matsuo Koji、Takazawa Yutaka、Ross Malcolm S.、Elishaev Esther、Yunokawa Mayu、Sheridan Todd B.、Bush Stephen H.、Klobocista Merieme M.、Blake Erin A.、Takano Tadao、Baba Tsukasa、Satoh Shinya、Shida Masako、Ikeda Yuji、et al.
  • Journal Title: Surgical Oncology Volume: 27 Issue: 3 Pages: 433-440
  • DOI: 10.1016/j.suronc.2018.05.017
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Proposal for a Risk-Based Categorization of Uterine Carcinosarcoma (2018)
  • Author(s): Matsuo Koji、Takazawa Yutaka、Ross Malcolm S.、Elishaev Esther、Yunokawa Mayu、Sheridan Todd B.、Bush Stephen H.、Klobocista Merieme M.、Blake Erin A.、Takano Tadao、Baba Tsukasa、Satoh Shinya、Shida Masako、Ikeda Yuji、et al.
  • Journal Title: Annals of Surgical Oncology Volume: 25 Issue: 12 Pages: 3676-3684
  • DOI: 10.1245/s10434-018-6695-z
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Significance of Lymphovascular Space Invasion by the Sarcomatous Component in Uterine Carcinosarcoma (2018)
  • Author(s): Matsuo Koji、Takazawa Yutaka、Ross Malcolm S.、Elishaev Esther、Yunokawa Mayu、Sheridan Todd B.、Bush Stephen H.、Klobocista Merieme M.、Blake Erin A.、Takano Tadao、Baba Tsukasa、Satoh Shinya、Shida Masako、Ikeda Yuji、et al.
  • Journal Title: Annals of Surgical Oncology Volume: 25 Issue: 9 Pages: 2756-2766
  • DOI: 10.1245/s10434-018-6547-x
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Snail promotes ovarian cancer progression by recruiting myeloid-derived suppressor cells via CXCR2 ligand upregulation. (2018)
  • Author(s): Taki M, Abiko K, Baba T, Hamanishi J, Yamaguchi K, Murakami R, Yamanoi K, Horikawa N, Hosoe Y, Nakamura E, Sugiyama A, Mandai M, Konishi I, Matsumura N.
  • Journal Title: Nature communications Volume: Apr 27;9(1) Issue: 1 Pages: 1685-1685
  • DOI: 10.1038/s41467-018-03966-7
  • NAID: 120006462510
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Significance of venous thromboembolism in women with uterine carcinosarcoma (2018)
  • Author(s): Matsuo Koji、Ross Malcolm S.、Im Dwight D.、Klobocista Merieme M.、Bush Stephen H.、Johnson Marian S.、Takano Tadao、Blake Erin A.、Ikeda Yuji、Nishimura Masato、Ueda Yutaka、Shida Masako、Hasegawa Kosei、et al.
  • Journal Title: Gynecologic Oncology Volume: 148 Issue: 2 Pages: 267-274
  • DOI: 10.1016/j.ygyno.2017.11.036
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Antitumor Effect of Nivolumab on Subsequent Chemotherapy for Platinum‐Resistant Ovarian Cancer (2018)
  • Author(s): Inayama Yoshihide、Hamanishi Junzo、Matsumura Noriomi、Murakami Ryusuke、Abiko Kaoru、Yamaguchi Ken、Baba Tsukasa、Horie Katsuyuki、Konishi Ikuo、Mandai Masaki
  • Journal Title: The Oncologist Volume: 23 Issue: 11 Pages: 1382-1384
  • DOI: 10.1634/theoncologist.2018-0167
  • Peer Reviewed / Int'l Joint Research
• [Presentation] What we have learned from gynecological endoscopic surgery for endometrial cancer. (2021)
  • Author(s): Baba T.
  • Organizer: The 21st APAGE Annual Congress (APAGE 2021)
  • Int'l Joint Research
• [Presentation] Gynecologic endoscopic treatment during the pandemic: Important considerations. (2021)
  • Author(s): Baba T.
  • Organizer: WISDOM 2021, the FOGSI - AOFOG - SAFOG Virtual Conference.
  • Int'l Joint Research / Invited
• [Presentation] Minimally invasive gynaecologic surgery– the new normal. (2021)
  • Author(s): Baba T.
  • Organizer: FIGO-AOFOG Global Webinar
  • Int'l Joint Research / Invited
• [Presentation] 婦人科腫瘍医の役割とは？：個別化治療を目指して (2018)
  • Author(s): 馬場 長
  • Organizer: 第9回奈良県婦人科腫瘍疾患研究会
  • Invited
• [Presentation] 高リスク子宮体癌、特に漿液性癌に対する新規治療法開発に向けた基礎研究. 第70回日本産科婦人科学会学術講演会シンポジウム婦人科がん治療戦略としての個別化医療の展開～基礎から臨床応用へ (2018)
  • Author(s): 馬場 長
  • Organizer: 第70回日本産科婦人科学会学術講演会
• [Presentation] Clinicopathologic features of ovarian serous borderline tumors with recurrence or extraovarian lesions; a retrospective multi-intuitional study of Japan Clinical Oncology Group (JCOG) (2018)
  • Author(s): Baba Tsukasa
  • Organizer: 17th Biennial Meeting of the International Gynecologic Cancer Society
  • Int'l Joint Research
• [Presentation] ESTABLISHMENT OF A MOUSE UTERINE SEROUS CARCINOMA MODEL (2018)
  • Author(s): Y. Mise , T. baba, R. murakami , K. abiko, J. hamanishi, N. matsumura , M. masaki
  • Organizer: 17th Biennial meeting of the International Gynecologic Cancer Society
  • Int'l Joint Research
• [Presentation] STAT1のリン酸化制御により子宮内膜漿液腺癌ノプラチナ抵抗性は克服できる (2018)
  • Author(s): 曽翔、馬場長、Budiman Kharma、松村謙臣、安彦郁、浜西潤三、三瀬有香、山口健、万代昌紀
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Establishment of an immunocompetent mouse endometrial cancer model of uterine Serous Carcinoma(USC) (2018)
  • Author(s): Yuka Mise,Tsukasa baba, Jyuzo Hamanishi, Kaoru Abiko, Ryusuke Murakami, Xiang, Khama Budiman, Noriomi Matsumura, Masaki Mandai
  • Organizer: 第77回日本癌学会学術総会