Genetic- and Somatic-regualtion of colorectal cancer
| Project/Area Number |
18H02684
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | Japanese Foundation for Cancer Research |
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Principal Investigator |
YAO Ryoji 公益財団法人がん研究会, がん研究所 細胞生物部, 部長 (80291095)
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| Co-Investigator(Kenkyū-buntansha) |
足立 淳 国立研究開発法人医薬基盤・健康・栄養研究所, 医薬基盤研究所 創薬デザイン研究センター, プロジェクトリーダー (20437255)
長山 聡 公益財団法人がん研究会, 有明病院 消化器外科, 医長 (70362499)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2020: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
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| Keywords | 患者由来オルガノイド / 大腸がん / KRAS / IFN/STATシグナル / MEK阻害剤 / 家族性大腸腺腫症 / 遺伝学的背景 / 遺伝的背景 / 体細胞変異 |
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| Outline of Final Research Achievements |
Familial adenomatous polyposis coli (FAP) is an autosomal-dominant inherited disease caused by ger- mline mutations in the adenomatous polyposis coli (APC) gene. FAP patients are classified into two major groups based on clinical manifestations: classical FAP (CFAP) and attenuated FAP (AFAP). In this study, we established 42 organoids from three CFAP patients and two AFAP patients. Comprehensive gene expression analysis demonstrated a close association between IFN/STAT signaling and the phenotypic features of FAP patients. Genetic disruption of Stat1 in the mouse model of FAP reduced tumor formation. We found that enhanced IFN/STAT signaling in CFAP conferred resistance to MEK inhibitors. These findings reveal the crosstalk between RAS signaling and IFN/ STAT signaling, which contributes to the tumor-forming potential and drug response. These results offer a rationale for targeting of IFN/STAT signaling and for the strati- fication of CRC patients.
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| Academic Significance and Societal Importance of the Research Achievements |
大腸がんは、遺伝子変異の蓄積により進展することが知られており、診断や治療法の選択の指標となっている。しかし、同一の遺伝子変異を持っていても転帰や化学療法の奏功率には、個人差がある。本研究では、遺伝的に多数の腫瘍を発生する家族性大腸腺腫症患者に生じた腫瘍からオルガノイドを樹立し、造腫瘍性と分子標的治療薬に対する感受性を検討した。その結果、遺伝的にIFN/STATシグナルが高い患者に生じた腫瘍は、造腫瘍性が高く、化学療法に対して抵抗性を示すことが明らかになった。
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Report
(4 results)
Research Products
(21 results)
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[Journal Article] Comparative Analysis of Patient-Matched PDOs Revealed a Reduction in OLFM4-Associated Clusters in Metastatic Lesions in Colorectal Cancer2021
Author(s)
Takuya Okamoto, David duVerle, Katsuyuki Yaginuma, Yasuko Natsume, Hitomi Yamanaka, Daisuke Kusama, Mayuko Fukuda, Mayuko Yamamoto, Yutaka Suzuki, Satoshi Nagayama, Ryoji Yao, et al.
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Journal Title
Stem Cell Reports
Volume: 16
Pages: 954-967
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Odf2 haploinsufficiency causes a new type of decapitated and decaudated spermatozoa, Odf2-DDS, in mice.2019
Author(s)
Ito C, Akutsu H, Yao R, Yoshida K, Yamatoya K, Mutoh T, Makino T, Aoyama K, Ishikawa H, Kunimoto K, Tsukita S, Noda T, Kikkawa M, Toshimori K.
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Journal Title
Sci Rep.3
Volume: 9
Pages: 14249-14249
DOI
Related Report
Peer Reviewed / Open Access
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