Adipocyte-mediated regulation of stem cell properties

• Project/Area Number: 23K21387
• Project/Area Number (Other): 21H02769 (2021-2023)
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Multi-year Fund (2024); Single-year Grants (2021-2023)
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Fujita Health University
• Principal Investigator: Shimono Yohei 藤田医科大学, 医学部, 教授 (90594630)
• Project Period (FY): 2024-04-01 – 2025-03-31
• Project Status: Completed (Fiscal Year 2024)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2024: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2023: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2022: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2021: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
• Keywords: がん幹細胞 / 組織幹細胞 / 脂肪細胞 / アディプシン / 乳腺組織発生 / 肝細胞増殖因子 / がん浸潤 / 肥満 / 乳がん / 組織発生 / がん転移 / 自然免疫 / アディポカイン / 卵巣がん

Outline of Research at the Start

組織には正常、悪性を問わず結合組織があり、発生や組織の維持に必須の役割を果たしている。脂肪細胞は代謝制御に加え結合組織の一員としても多彩な役割をもつが、その働きは必ずしも明らかではない。本研究では、脂肪細胞が「幹細胞性」の制御を通じて正常組織形成、がん発生、およびがん転移の三局面で働く仕組みを解明する。多面的解析により幹細胞制御因子としての脂肪細胞の意義を明らかにすることで、脂肪細胞とその分泌因子を標的としたがん治療を実現するための基礎データを得る。

Outline of Final Research Achievements

Adipocytes not only play roles in energy storage and metabolism but also regulate biological functions through the secretion of various factors known as adipokines. This study found that the adipocyte secretory factor adipsin acts as an autocrine regulator to promote the secretion of hepatocyte growth factor (HGF) from adipocytes. It was also discovered that adipsin and HGF cooperatively enhance cancer stem cell properties and that adipsin promotes adipocyte maturation. Furthermore, the study showed that adipsin-dependent adipocyte maturation is a strong promoter of cancer cell invasion and metastasis, and revealed a part of the molecular mechanisms by which mature adipocytes promote cancer progression.

Academic Significance and Societal Importance of the Research Achievements

近年の世界的な肥満者の増加とともに、脂肪細胞の異常蓄積が乳がん、大腸がん、卵巣がんなど各種のがんを促進する機構の解明が求められている。脂肪細胞によるがん悪性化機構としては、脂肪組織内に起こる慢性炎症、脂肪細胞からのエネルギー供給によるがん細胞活性化、脂肪細胞による抗がん剤の不活化促進などが挙げられてきた。本研究は、脂肪細胞の分泌因子アディプシンと肝細胞増殖因子ががん幹細胞性を促進することを明らかにするとともに、脂肪細胞の成熟分化が強力ながん進展促進因子であることを示した。本研究の成果は、脂肪細胞蓄積により悪性化する幅広いがんに対し、新たな治療標的分子候補を提供する点でも意義がある。

Research Products

• [Int'l Joint Research] モンペリエがん研究所(フランス)
• [Int'l Joint Research] モンペリエがん研究所(フランス)
• [Int'l Joint Research] モンペリエがん研究所(フランス)
• [Int'l Joint Research] コロンビア大学(米国)
• [Int'l Joint Research] モンペリエがん研究所(フランス)
• [Journal Article] Estrogen synthesized in the central nervous system enhances MC4R expression and reduces food intake (2025)
  • Author(s): Hayashi Takanori、Kumamoto Kanako、Kobayashi Tatsuya、Hou Xinfeng、Nagao Shizuko、Harada Nobuhiro、Honda Shinichiro、Shimono Yohei、Nishio Eiji
  • Journal Title: The FEBS Journal Volume: - Issue: 15 Pages: 1-10
  • DOI: 10.1111/febs.17426
  • Peer Reviewed / Open Access
• [Journal Article] Adipsin-dependent adipocyte maturation induces cancer cell invasion in breast cancer (2024)
  • Author(s): Yoshida J, Hayashi T, Munetsuna E, Khaledian B, Sueishi F, Mizuno M, Maeda M, Watanabe T, Ushida K, Sugihara E, Imaizumi K, Kawada K, Asai N, Shimono Y
  • Journal Title: Scientific Reports Volume: 14(1) Issue: 1 Pages: 18494-18494
  • DOI: 10.1038/s41598-024-69476-3
  • Peer Reviewed / Open Access
• [Journal Article] CYP19A1 expression is controlled by mRNA stability of the upstream transcription factor AP-2γ in placental JEG3 cells (2024)
  • Author(s): Kotomura Naoe、Shimono Yohei、Ishihara Satoru
  • Journal Title: Endocrinology Volume: 2024 Issue: 6
  • DOI: 10.1210/endocr/bqae055
  • Peer Reviewed / Open Access
• [Journal Article] Adipocyte regulation of cancer stem cells (2023)
  • Author(s): Khaledian Behnoush、Thibes Lisa、Shimono Yohei
  • Journal Title: Cancer Science Volume: 114 Issue: 11 Pages: 4134-4144
  • DOI: 10.1111/cas.15940
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Monocyte-Derived miRNA-1914-5p Attenuates IL-1β?Induced Monocyte Adhesion and Transmigration (2023)
  • Author(s): Toriuchi Kohki、Kihara Toshie、Aoki Hiromasa、Kakita Hiroki、Takeshita Satoru、Ueda Hiroko、Inoue Yasumichi、Hayashi Hidetoshi、Shimono Yohei、Yamada Yasumasa、Aoyama Mineyoshi
  • Journal Title: International Journal of Molecular Sciences Volume: 24 Issue: 3 Pages: 2829-2829
  • DOI: 10.3390/ijms24032829
  • Peer Reviewed / Open Access
• [Journal Article] Upregulation of BMI1-suppressor miRNAs (miR-200c, miR-203) during terminal differentiation of colon epithelial cells (2022)
  • Author(s): Hisamori Shigeo、Mukohyama Junko、Koul Sanjay、Hayashi Takanori、Rothenberg Michael Evan、Maeda Masao、Isobe Taichi、Valencia Salazar Luis Enrique、Qian Xin、Johnston Darius Michael、Qian Dalong、Lao Kaiqin、Asai Naoya、Kakeji Yoshihiro、Gennarino Vincenzo Alessandro、Sahoo Debashis、Dalerba Piero、Shimono Yohei
  • Journal Title: Journal of Gastroenterology Volume: Online ahead of print Issue: 6 Pages: 407-422
  • DOI: 10.1007/s00535-022-01865-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Adipsin-Dependent Secretion of Hepatocyte Growth Factor Regulates the Adipocyte-Cancer Stem Cell Interaction (2021)
  • Author(s): Mizuno Masahiro、Khaledian Behnoush、Maeda Masao、Hayashi Takanori、Mizuno Seiya、Munetsuna Eiji、Watanabe Takashi、Kono Seishi、Okada Seiji、Suzuki Motoshi、Takao Shintaro、Minami Hironobu、Asai Naoya、Sugiyama Fumihiro、Takahashi Satoru、Shimono Yohei
  • Journal Title: Cancers Volume: 13 Issue: 16 Pages: 4238-4238
  • DOI: 10.3390/cancers13164238
  • Peer Reviewed / Open Access
• [Presentation] Adipsin dependent adipocyte maturation promotes breast cancer invasion. (2024)
  • Author(s): Yohei Shimono, Jumpei Yoshida, Takanori Hayashi, Eiji Munetsuna, Behnoush Khaledian, Yuko Kijima, Naoya Asai, Kenji Kawada.
  • Organizer: 第21回 幹細胞シンポジウム
• [Presentation] γ-グルタミルシクロトランスフェラーゼによるがん幹細胞性促進 (2024)
  • Author(s): 下野洋平、林孝典、末石布志子、南博信、喜島祐子、鈴木元、浅井直也、Andrei Turtoi
  • Organizer: 第１０回がんと代謝研究会
• [Presentation] Adipocyte regulation of cancer stem cells and their metastatic progression. (2024)
  • Author(s): Yohei Shimono, Masahiro Mizuno, Takanori Hayashi, Behnoush Khaledian, Fujiko Sueishi, Kaori Ushida, Yasuyoshi Mizutani, Hironobu Minami, Kenji Kawada, Motoshi Suzuki, Naoya Asai
  • Organizer: 第83回日本癌学会学術総会
  • Invited
• [Presentation] Adipokine Adipsin promotes tumor invasion by upregulation of matrix metalloproteinase-9 and Lgalectin-7 in Breast Cancer (2024)
  • Author(s): Behnoush Khaledian, Takanori Hayashi, Masahiro Mizuno, Masao Maeda, Takashi Watanabe, Kaori Ushida, Eiji Sugihara, Kenji Kawada, Naoya Asai, Yohei Shimono
  • Organizer: 第83回日本癌学会学術総会
• [Presentation] Roles of gamma-glutamylcyclotransferase variants in tumor proliferation and drug resistance in breast cancer. (2024)
  • Author(s): Raito Sugiura, Takanori Hayashi, Fujiko Sueishi, Yohei Shimono
  • Organizer: 第83回日本癌学会学術総会
• [Presentation] Adipsin-dependent adipocyte maturation induces cancer cell invasion (2024)
  • Author(s): 下野洋平、吉田淳平、林孝典、宗綱栄二、ベフヌーシュ・ハレディアン、末石布志子、河田健司、浅井直也
  • Organizer: 第35回日本消化器癌発生学会総会
• [Presentation] Identification of the epigenetic mechanism for colorectal cancer stem cell regulation through the comprehensive microRNA expression profiling of human colorectal cancer tissues. (2023)
  • Author(s): Mukohyama J, Itano O, Kakej Y, Shimono Y
  • Organizer: ASCO Breakthrough
  • Int'l Joint Research
• [Presentation] Adipocytes promote cancer stem cell properties and metastatic progression of breast cancer cells through adipsin. (2023)
  • Author(s): Khaledian B, Yoshida J, Mizuno M, Maeda M, Hayashi T, Munetsuna E, Mizuno S, Mizutani Y, Okada S, Suzuki M, Sugiyama F, Takahashi S, Asai N, Kawada K, Shimono Y
  • Organizer: 第20回 幹細胞シンポジウム
• [Presentation] γ-Glutamylcyclotransferase, a novel regulator of cancer stem cell properties in breast cancer. (2023)
  • Author(s): Hayashi T, Okada S, Hirata M, Mizutani Y, Kijima Y, Suzuki M, Shimono Y
  • Organizer: 第20回 幹細胞シンポジウム
• [Presentation] 脂肪細胞分泌因子アディプシンによるがん幹細胞性促進作用 (2023)
  • Author(s): Shimono Y, Khaledian B, Mizuno M, Yoshida J, Gotoh N, Kawada K.
  • Organizer: 第9回がんと代謝研究会
• [Presentation] 脂肪細胞によるがん幹細胞性制御機構 (2023)
  • Author(s): Shimono Y, Goto H, Hayashi T, Khaledian B, Maeda M, Shibuya N, Kono S, Funakoshi Y, Kakeji Y, Minami H.
  • Organizer: 第34回日本消化器癌発生学会総会
• [Presentation] Adipsin-dependent adipocyte differentiation promotes the adipocyte-breast cancer stem cell interactions. (2023)
  • Author(s): Khaledian B, Yoshida J, Hayashi T, Mizuno M, Ushida K, Maeda M, Munetsuna E, Kawada K, Asai N, Shimono Y
  • Organizer: 第82回日本癌学会学術総会
• [Presentation] Lack of adipokine adipsin suppresses breast cancer invasion and metastasis. (2023)
  • Author(s): Hayashi T, Yoshida J, Munetsuna E, Khaledian B, Ushida K, Mizuno M, Maeda M, Asai N, Kawada K, Shimono Y
  • Organizer: 第82回日本癌学会学術総会
• [Presentation] γ-Glutamylcyclotransferase enhances cancer stem cell properties in breast cancer. (2023)
  • Author(s): Sakai H, Hayashi T, Hirata M, Mizutani Y, Okada S, Kijima Y, Suzuki M, Shimono Y
  • Organizer: 第82回日本癌学会学術総会
• [Presentation] Lower expression of Rab31 confers cancer stem cell properties and therapeutic resistance to the CDK4/6 inhibitor in breast cancer. (2023)
  • Author(s): Hou X, Hayashi T, Mizutani Y, Okada S, Suzuki M, Shimono Y
  • Organizer: 第82回日本癌学会学術総会
• [Presentation] 脂肪細胞による乳がん幹細胞性促進機構 (2023)
  • Author(s): Shimono Y, Mizuno M, Khaledian B, Goto H, Yoshida J, Funakoshi Y, Hayashi T, Munetsuna E, Maeda M, Asai N, Minami H, Kawada K
  • Organizer: 第20回日本臨床腫瘍学会学術集会
• [Presentation] Adipokine adipsin enhances the adipocyte-breast cancer stem cell interaction. (2022)
  • Author(s): Shimono Y, Mizuno M, Khaledian B, Goto H, Funakoshi Y, Maeda M, Hayashi T, Mizuno S, Okada S, Kijima Y, Suzuki M, Asai N, Sugiyama F, Takahashi S, Minami H
  • Organizer: The12th AACR-JCA Joint Conference
  • Int'l Joint Research
• [Presentation] Distantly metastasized cancer stem cells in human breast cancer xenograft mouse. (2022)
  • Author(s): Shimono Y, Hayashi T, Kono S, Shibuya N, Hisamori S, Mukohyama J, Yanagi H, Watanabe T, Maeda M, Hirata M, Kakeji Y, Kawada K, Asai N, Okada S, Suzuki M, Takao S, Minami H, Kijima Y, Gotoh N, Dalerba P
  • Organizer: The 6 th International Workshop on Humanized Mice
  • Int'l Joint Research / Invited
• [Presentation] Hepatocyte growth factor is an adipokine that enhances breast cancer stem cell properties. (2022)
  • Author(s): Khaledian B, Mizuno M, Maeda M, Hayashi T, Mizuno S, Okada S, Suzuki M, Asai N, Sugiyama F, Takahashi S, Shimono Y
  • Organizer: 第19回 幹細胞シンポジウム
• [Presentation] γ-グルタミルシクロ転移酵素による乳がん幹細胞制御機構 (2022)
  • Author(s): Shimono Y, Hayashi T, Maeda M, Asai N, Turtoi A, Soga Y
  • Organizer: 第8回 がんと代謝研究会
• [Presentation] MicroRNA-mediated suppression of colon cancer stemness by the induction of terminal differentiation. (2022)
  • Author(s): Shimono Y, Hisamori S, Mukohyama J, Isobe T, Kakeji Y, Dalerba P
  • Organizer: 第33回日本消化器癌発生学会総会
• [Presentation] Adipsin functions as promoter of the adipocyte-breast cancer stem cell interaction in the terminally differentiated adipocytes. (2022)
  • Author(s): Khaledian B, Mizuno M, Maeda M, Munetsuna E, Yoshida J, Asai N, Shimono Y
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] Rab31 is a potential biomarker and a negative regulator of a CDK4/6 inhibitor Palbociclib resistance in breast cancers. (2022)
  • Author(s): Hou X, Hayashi T, Harada N, Shimono Y
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] Adipokine DPP4 enhances cancer stem cell-like properties in ovarian cancer. (2022)
  • Author(s): Maeda M, Nishio E, Hayashi T, Khaledian B, Ushida K, Okada S, Suzuki M, Asai N, Fujii T, Saya H, Shimono Y
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] Analyses of terminally differentiated normal cells guide the identification of cancer stem cell-suppressor microRNAs. (2022)
  • Author(s): Shimono Y, Hisamori S, Mukohyama J, Isobe T, Kakeji Y, Dalerba P
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] Role of S100A10 in the metastatic colonization of breast cancer stem cells. (2021)
  • Author(s): Shimono Y, Yanagi H, Watanabe T, Nishimura T, Hayashi T, Okada S, Suzuki M, Kawada K, Minami H, Gotoh N.
  • Organizer: AACR Virtual Annual Meeting 2021
  • Int'l Joint Research
• [Presentation] miR-93 targets WASF3 and functions as a metastasis suppressor in human breast cancer stem cells. (2021)
  • Author(s): Shimono Y, Shibuya N, Nishimura T, Gotoh N, Kakeji Y.
  • Organizer: 第18回 幹細胞シンポジウム
• [Presentation] Application of organoids to breast cancer research. (2021)
  • Author(s): Shimono Y, Nishimura T, Kono S, Shibuya N, Yanagi H, Hayashi T, Watanabe T, Maeda M, Kakeji Y, Kawada K, Asai N, Takao S, Minami H, Kijima Y, Suzuki M, Gotoh N.
  • Organizer: 第80回日本癌学会学術総会
  • Invited
• [Presentation] Autocrine regulation of adipocytes promotes cancer stem cell properties in breast cancers. (2021)
  • Author(s): Khaledian B, Mizuno M, Maeda M, Takusagawa S, Yano M, Asai N, Shimono Y.
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] Adipsin-dependent HGF secretion from adipocytes promotes cancer stem cell properties in breast cancer cells. (2021)
  • Author(s): Mizuno M, Khaledian B, Maeda M, Takusagawa S, Yano M, Asai N, Shimono Y.
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] Adipocytes secrete DPP4 and enhance ovarian cancer stem cell-like properties in ovarian cancer. (2021)
  • Author(s): Takusagawa S, Maeda M, Yano M, Nishio E, Okada S. Suzuki M, Asai N, Fujii T, Saya H, Shimono Y.
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] Adipocytes enhance cancer stem cell-like properties in ovarian cancers through MCP1. (2021)
  • Author(s): Yano M, Maeda M, Nishio E, Takusagawa S, Suzuki M, Asai N, Fujii T, Saya H, Shimono Y.
  • Organizer: 第80回日本癌学会学術総会
• [Remarks] 藤田医科大学医学部生化学講座
  • URL: http://www.fujita-hu.ac.jp/~biochem1/index.html
• [Remarks] 藤田医科大学生化学講座
  • URL: http://www.fujita-hu.ac.jp/~biochem1/index.html
• [Patent(Industrial Property Rights)] 抗がん剤 (2021)
  • Inventor(s): 下野洋平、佐谷秀行、前田真男
  • Industrial Property Rights Holder: 下野洋平、佐谷秀行、前田真男
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2021-137508
  • Filing Date: 2021