| Project/Area Number |
17K16050
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | Kumamoto University |
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Principal Investigator |
Matsuo Akira 熊本大学, 大学院生命科学研究部(医), 研究員 (50735074)
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 運命転換 / 幹細胞 / 肺癌 / 直接運命転換 / 発生医学 / 肺腺癌 |
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| Outline of Final Research Achievements |
Transformation of EGFR mutant lung adenocarcinoma to small cell lung carcinoma is known to one of the major resistant mechanisms for EGFR tyrosine kinase inhibitors (TKIs). However, little is known about the mechanism underlying the transformation of adenocarcinoma to small cell lung carcinoma. Here, we show that club cells (a cell origin of adenocarcinoma) convert into neuroendocrine cells (a cell origin of small cell lung carcinoma) in the developing and adult lung. Using stringent lineage tracing, club cells gave rise to neuroendocrine cells before E14.5. But after E14.5, we did not observe lineage-labeled cells expressing the neuroendocrine cell maker CGRP, suggesting that club cells lost their ability to generate neuroendocrine cells. Furthermore, we found that Hes1 loss club cells convert into neuroendocrine cells after E14.5 and adulthood. Taken together, these results reveal that Hes1 inactivation can induce the lineage conversion of club cells into neuroendocrine cells.
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| Academic Significance and Societal Importance of the Research Achievements |
分子標的薬耐性獲得機構の一つとして、腺癌が小細胞癌に転換する症例が報告されており、その転換機構は不明な点が大きかった。今回、本研究において、肺腺癌の起源細胞の１つであるClub細胞から神経内分泌細胞への運命転換にHes1の不活性化が関与していることが明らかになった。本研究の知見は、恒常性及び癌におけるClub細胞の直接運命転換の理解及び組織型転換癌（耐性獲得癌）に対する新たな分子標的薬開発の基盤となる。さらに、組織型転換癌及び混合型癌における異なる組織型癌を生み出す癌起源細胞の分子機構解明へ貢献できる。
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