Functional single-cell analysis of the stem cell plasticity associated with drug-tolerant persister cells in colorectal cancer
与结直肠癌耐药持久细胞相关的干细胞可塑性的功能单细胞分析
基本信息
- 批准号:22K15539
- 负责人:
- 金额:$ 2.91万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Early-Career Scientists
- 财政年份:2022
- 资助国家:日本
- 起止时间:2022-04-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Using patient-derived colorectal cancer (CRC) organoids, we previously generated an analysis platform consisting of slow-growing CRC cells isolated from different human samples to represent the tumor heterogeneity. In this study, we tracked the fate of each cell through a clonogenic growth assay and found that the CRC cells showed a wide range of growth ability. Further rounds of the clonogenic growth assay revealed that the spheroid forming cells in CRC organoids consisted of distinct subpopulations; the cells generating large spheroids (L-cells) and the cells generating small spheroids (S-cells). The cells derived from the small spheroids gave rise to only small spheroids, consisting of slow-growing cells (S-pattern). While the cells derived from the large spheroids gave rise to both small and large spheroids, showing a dual-growing phenotype (D-pattern). Although the S-pattern spheroids never gave rise to large spheroids once isolated, transition to the D-pattern occurred by various extrinsic triggers, in which Musashi-1 (MSI1) played a key role. We revealed that the suppression of MSI1 in large spheroids, by using the CRISPR/Cas9 system, induced a transition from the D- to the S-pattern. We also found that the S-pattern spheroids were resistant to chemotherapy and transited to the D-pattern upon drug treatment. In conclusion, the isolated S-cells could be a novel platform for investigating drug-tolerant persister cells (DTPs) and developing the DTP targeting treatment. As the transition is linked to the drug resistance, it can be a therapeutic target.
使用患者来源的结直肠癌(CRC)类器官,我们先前生成了一个分析平台,该平台由从不同人类样本中分离的缓慢生长的CRC细胞组成,以代表肿瘤异质性。在这项研究中,我们通过克隆生长试验跟踪每个细胞的命运,发现CRC细胞显示出广泛的生长能力。进一步的克隆生长试验显示,CRC类器官中的球状体形成细胞由不同的亚群组成;产生大球状体(L细胞)的细胞和产生小球状体(S细胞)的细胞。来源于小球体的细胞仅产生小球体,由生长缓慢的细胞组成(S型)。而大球体衍生的细胞产生小球体和大球体,显示出双生长表型(D型)。虽然S型球状体一旦分离就不会产生大的球状体,但是通过各种外部触发器发生了向D型球状体的转变,其中Musashi-1(MSI 1)发挥了关键作用。我们发现,通过使用CRISPR/Cas9系统抑制大球体中的MSI 1,诱导了从D-到S-模式的转变。我们还发现S型球状体对化疗耐药,药物治疗后转变为D型。总之,分离的S-细胞可能是研究耐药持续细胞(DTP)和开发DTP靶向治疗的新平台。由于这种转变与耐药性有关,因此它可以成为治疗靶点。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Subpopulations with distinct and interchangeable capacity of spheroid formation and growth in colorectal cancer
结直肠癌中具有独特且可互换的球体形成和生长能力的亚群
- DOI:
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Roberto Coppo;Jumpei Kondo;Kunishige Onuma;Masahiro Inoue
- 通讯作者:Masahiro Inoue
Distinct and Interchangeable Subpopulations of CRC by a Functional Single Cell Analysis
通过功能性单细胞分析确定不同且可互换的 CRC 亚群
- DOI:
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Roberto Coppo;Kunishige Onuma;Jumpei Kondo;Masahiro Inoue
- 通讯作者:Masahiro Inoue
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