2022 Fiscal Year Final Research Report
The mechanism of polarity switching in the cluster of human colorectal adenocarcinoma during the process of metastasis
| Project/Area Number |
20K08286
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53010:Gastroenterology-related
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
井上 正宏 京都大学, 医学研究科, 特定教授 (10342990)
近藤 純平 大阪大学, 大学院医学系研究科, 准教授 (80624593)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | がん細胞集団の極性転換 / がん細胞集団の転移 / 大腸癌オルガノイド / 血管内皮との接着 / 活性酸素 / micropapillary carcinoma / 薬剤感受性と極性転換 |
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| Outline of Final Research Achievements |
The metastatic mechanism of the cancer cells cluster remains unclear. In this study, we showed that the apical-out status of colorectal cancer cells might be advantageous during the extravasation step of metastasis through discharged ROS from the apical membrane of cancer cell clusters. In addition, CFTR inhibitor172 was identified as a candidate compound that inhibits the polarity switching from apical-in to apical-out. In order to focus on the therapeutic strategy to inhibit metastasis through polarity switching, we used MPC-organoids. MPC-organoids exhibited apical-out polarity, even when embedded in the extracellular matrix (ECM). We identified Factor-X, a cytokine that can mitigate the apical-out polarity of MPCs in ECM. Combination of Factor-X and anticancer drugs enhanced drug sensitivity in vitro. In summary, this project is expected to elucidate the metastatic mechanism of cancer cell clusters and to demonstrate the possibility of inhibiting metastasis by polarity switching.
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| Free Research Field |
腫瘍学
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| Academic Significance and Societal Importance of the Research Achievements |
大腸がん細胞の多くは原発巣・転移巣ともに細胞集団として存在するにも関わらず、単細胞としての研究が多い。近年では癌の浸潤においては病理学的観察に基づいて細胞が集団として浸潤するモデルや、細胞集団が転移の起源となるモデルが提唱されているが、分化型腺癌の集団特性を維持できる培養法がこれまでにほとんど存在しなかったために、集団としてのがん細胞の振る舞いについては、未だ不明な点が多い。本研究で明らかとしたapical-outの極性状態の持つ転移における役割とメカニズムの解析および極性の観点からの治療・転移の抑制に結び付けるための化合物の同定は、癌の転移研究にとって大きな意義があると考えられる。
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