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

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.
利用患者来源的结直肠癌(CRC)类器官,我们之前建立了一个分析平台,该平台由从不同人类样本中分离的生长缓慢的CRC细胞组成,以代表肿瘤的异质性。在这项研究中,我们通过克隆生长试验追踪了每个细胞的命运,发现CRC细胞表现出广泛的生长能力。进一步的克隆生长试验显示,CRC类器官中的球状形成细胞由不同的亚群组成;产生大球体的细胞(l细胞)和产生小球体的细胞(s细胞)。由小球体衍生的细胞只产生小球体,由生长缓慢的细胞组成(s型)。而来源于大球体的细胞可同时产生小球体和大球体,呈现双生长表型(d型)。虽然s型球体一旦被分离就不会产生大的球体,但向d型的转变是由各种外在触发因素引起的,其中Musashi-1 (MSI1)起了关键作用。我们发现,通过使用CRISPR/Cas9系统,在大球体中抑制MSI1诱导了从D-模式到s模式的转变。我们还发现s型球体对化疗有耐药性,并在药物治疗后转变为d型。综上所述,分离的s细胞可作为研究耐药持久性细胞(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,因此可以作为治疗靶点。

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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