2020 Fiscal Year Final Research Report
Investigation of the roles of bone marrow-derived fibroblasts/myofibroblasts and their molecular mechanism in the carcinogenesis of mouse models of pancreatic cancer
| Project/Area Number |
17K09460
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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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| Research Field |
Gastroenterology
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2021-03-31
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| Keywords | 膵癌発症マウス / ヒト及びマウス膵癌培養細胞株 / ヒト膵癌オルガノイド / COX-1, -2遺伝子 / CAGE法 / 膵癌幹細胞 / 上皮間葉転換(EMT) / SNAIL2(別称SLUG) |
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| Outline of Final Research Achievements |
We changed the research subjects to the following new ones: A) Characterization of our newly established two murine pancreatic cancer cell lines: a) from pancreatic intraepithelial neoplasia (PanIN), b) from intraductal papillary-mucinous neoplasm (IPMN). B) Investigation of molecular mechanism of epithelial-mesenchymal transition (EMT) in human pancreatic cancer by using pancreatic cancer cell lines (PCLs) and patient-derived pancreatic cancer organoids (PDOs).
We obtained following results: A) The transcriptome of PanIN cells exhibited properties of stemness, while that of IPMN cells was enriched for PI3K/Akt signal-related genes. Various transcriptional factor networks in PanIN and IPMN cells reflect the distinct molecular profiles of these cell types. B) Among EMT-related transcriptional factors, SNAIL2 is most highly expressed in PCLs as well as PDOs. Suppression of SNAIL2 decreased tumorigenicity, and microarray analysis revealed the mechanism was mainly mediated by IGFBP2.
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| Free Research Field |
消化器癌幹細胞
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| Academic Significance and Societal Importance of the Research Achievements |
膵癌の5年相対生存率は男女平均で約8.5％であり、全癌腫中で最低の数値である。従って、膵癌の発癌機構を解明し新たな治療戦略を見出すことは現在の癌診療政策における喫緊の課題であると言える。
今回の研究成果は、PanINとIPMNで異なる転写因子ネットワークが機能しており、前者で幹細胞関連因子が高発現し、後者ではPI3K/Aktシグナルが亢進していることを示した。加えて、ヒト膵癌においてEMT関連因子であるSNAIL2の発現を抑制することにより、癌幹細胞分画が縮小し抗癌剤への抵抗性が減弱すること、従ってSNAIL2およびその主たる下流遺伝子であるIGFBP2が新規の治療標的となることが期待される。
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