Single-cell gene expression analysis reveals the cellular heterogeneity of colon tumors and identifies novel therapeutic target genes

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07283
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: National Cancer Center Japan
• Principal Investigator: Shiokawa Daisuke 国立研究開発法人国立がん研究センター, 研究所, ユニット長 (90277278)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: シングルセル / がん幹細胞

Outline of Final Research Achievements

LGR5 is an established stem cell marker gene in many digestive tissues, and we previously showed that a subpopulation of LGR5+ cells in colon tumors were responsible for tumorigenicity. In this study, we demonstrated that the tumorigenic subpopulation of mouse LGR5+ cells exist in a quiescent state, and identified a unique gene signature that characterize these quiescent CSCs. Furthermore, seven of the signature genes are specifically expressed in a quiescent LGR5+ cells from xenografted human colon tumors and upregulated in colon cancer clinical specimens. Among these seven, PROX1 is expressed in invasive fronts of colon tumors, and shown to be induced by TCF7 to maintain a quiescent state. Importantly, PROX1 knockout significantly reduces tumor recurrence after chemotherapeutic treatment. The identified slow-cycling CSC signatures will be instrumental in targeting the chemoresistant CSCs and devising effective chemotherapy.

Free Research Field

がん生物学

Academic Significance and Societal Importance of the Research Achievements

本研究の成果により、これまで不明であったLGR5陽性幹細胞群の細胞多様性が明らかなり、当該細胞集団が増殖型と休止型の２種に大別されることが示された。さらに休止型がん幹細胞で特異的に発現する遺伝子であるPROX1の機能を抑制することにより抗癌剤への感受性を高めることに成功した。即ち、本件研究の成果として得られた知見は、がん本態解明を目指す基礎研究としてのみならず、効果的ながん治療法の開発の礎となり社会に貢献する大きな意義を持つ研究成果であると考えられる。