Cellular context-dependent consequences of Apc mutations on gene regulation and cellular behavior

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K10540
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kyoto University
• Principal Investigator: Hashimoto Kyoichi 京都大学, 医学研究科, 客員研究員 (00769424)
• Research Collaborator: Yamada Yasuhiro
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 癌 / エピジェネティクス

Outline of Final Research Achievements

The spectrum of genetic mutations differs among cancers in different organs,implying a cellular context-dependent effect for genetic aberrations. However,the extent to which the cellular context affects the consequences of oncogenic mutations remains to be fully elucidated.We reprogrammed colon tumor cells in an ApcMin/+ mouse model,in which the loss of the Apc gene plays a critical role in tumor development and subsequently,established reprogrammed tumor cells(RTCs).The redisruption of Apc in RTC-derived differentiated cells resulted in neoplastic growth that was exclusive to the intestine,but the majority of pretumoral microadenomas.These results highlight the significant influence of cellular context on gene regulation,cellular plasticity,and cellular behavior in response to the loss of the Apc function.Our results also imply that the transition from microadenomas to macroscopic tumors is reprogrammable,which underscores the importance of epigenetic regulation on tumor promotion.

Free Research Field

消化器外科

Academic Significance and Societal Importance of the Research Achievements

従来、癌の発生や進展には多段階発癌に代表されるように遺伝子の異常が深く関与することが知られていたがエピゲノムの関与については議論の余地が残っていた。今回、エピゲノム制御が癌の発生・進展に影響することを実験動物モデルを用いて示し、癌の発生・進展におけるエピゲノムの関与解明に貢献し、癌の新しい治療戦略の構築に寄与するところが多いと考えられた。