Spatial and temporal analysis of human colon cancer stem cells using 4D imaging

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K17030
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Keio University
• Principal Investigator: Ohta Yuki 慶應義塾大学, 医学部(信濃町), 研究員 (80867549)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 大腸癌 / 幹細胞 / がん幹細胞 / 休止細胞

Outline of Final Research Achievements

Cancer relapse after chemotherapy remains a main cause of cancer-related death. Although the relapse is thought to result from the propagation of resident cancer stem cells (CSCs), a lack of experimental platforms that enable prospective analysis of CSC dynamics has hindered testing of this hypothesis. Here, we develop a live genetic lineage-tracing system that allows longitudinal tracking of individual cells in xenotransplanted human colorectal cancer organoids and identify CSCs that display a dormant behavior in a chemo-naive state. Intravital imaging directly demonstrates the persistence of dormant CSCs during chemotherapy, followed by clonal expansion. Transcriptome analysis reveals an up-regulation of cell adhesion molecule in dormant CSCs. Chemotherapy disrupts cell adhesion molecule and induces the breaking of dormancy in CSCs. These results offer a viable therapeutic approach to overcome refractoriness of human colorectal cancer to conventional chemotherapy.

Free Research Field

消化器腫瘍

Academic Significance and Societal Importance of the Research Achievements

消化器がんの根治治療開発には、化学療法耐性と腫瘍再構築能を併せもつ「がん幹細胞」の理解が必要である。がん幹細胞の増殖動態を解き明かすためには時間軸に沿った動的な解析が不可欠である一方、実験基盤の欠如により生体内でのがん幹細胞動態についてはブラックボックスであった。本研究では臨床消化器がんの培養技術、幹細胞の増殖動態を可視化する革新的な遺伝子編集技術及び多光子顕微鏡を用いた生体イメージング技術により、腫瘍維持と薬剤抵抗、再発のそれぞれのフェーズにおけるがん幹細胞の時空間ダイナミクスの解明を達成した。本研究成果は消化器がんの再発・転移メカニズムの理解を深め、根源治療法の開発に繋がると期待される。