Project 1: Interrogating Distinct Tumor-Initiating Cells in CRC

项目 1：研究 CRC 中不同的肿瘤起始细胞

• 批准号: 10700848
• 负责人: Robert J. Coffey
• 金额: $ 38.94万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-09 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10700848
• 关键词: Ablation; Affect; Aftercare; Alleles; Architecture; Behavior; Cancer Center; Cancer Model; Cancer Prognosis; Cells; Cellular biology; Characteristics; Classification; Clinical Trials; Colon; Colon Carcinoma; Colonoscopy; Colorectal Cancer; Dependence; Distal; EGF gene; Epidermal Growth Factor Receptor; Fluorouracil; Goals; Homeostasis; Human; Immunofluorescence Immunologic; Individual; LGR5 gene; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Maps; Modeling; Monitor; Monoclonal Antibodies; Mus; Optics; Organoids; Pathway interactions; Patients; Play; Population; Primary Neoplasm; Property; Recurrent Malignant Neoplasm; Recurrent tumor; Reporter Genes; Role; Sampling; Signal Transduction; Site; System; Testing; Therapeutic; Therapeutic Intervention; Time; Tissue Microarray; Tissues; Translating; Treatment Efficacy; Work; cancer cell; cancer recurrence; cancer stem cell; cancer therapy; cell behavior; chemotherapy; combinatorial; conventional therapy; design; in vivo; irinotecan; molecular marker; novel; patient response; predicting response; predictive modeling; prognostic; prospective; repository; response; single cell technology; single-cell RNA sequencing; stem; stem cell population; stem cells; therapy resistant; tool; transcriptomics; translational goal; treatment response; tumor; tumor growth; tumor initiation; tumorigenic

PROJECT SUMMARY/ABSTRACT: P1. Interrogating Distinct Tumor-Initiating Cells A major therapeutic barrier in advanced colorectal cancer (CRC) is tumor recurrence after treatment. The “cancer stem cell hypothesis” posits that rare populations of cancer cells with stem cell characteristics, also known as tumor-initiating cells (TICs), fuel tumor growth, resist therapy, and repopulate the tumor at distal sites. In the normal colon, multiple stem cell populations exist in a reserve-to-active continuum. We hypothesize that distinct TIC populations exist in CRC, and these distinct populations of TICs have different clonogenic properties and tumor-repopulating potential. Using TICs marked by Lrig1 and Lgr5 to represent reserve and active TICs, respectively, we will use novel single-cell approaches to investigate the behaviors of these populations in the context of therapeutic intervention. First, we will determine whether there is a defined directional hierarchy where reserve TICs give rise to active TICs versus mutual interconversion. Second, we will determine whether TICs with malignant characteristics pre-exist in the primary tumor or if TICs acquire these characteristics de novo as a result of treatment. Third, we will determine whether a signature derived from TIC behaviors provides prognostic and/or predictive information for individuals with CRC. Our translational goal is to apply a systems approach to predict likelihood of tumor recurrence based on properties of TIC populations with the long-term goal of using combinatorial pathway alterations to target TIC behaviors.

项目摘要/摘要：P1。询问不同的肿瘤发射细胞 晚期结直肠癌（CRC）的主要热屏障是治疗后的肿瘤复发。这 “癌症干细胞假设”认为，具有干细胞特征的癌细胞的罕见种群也 被称为肿瘤发射细胞（TICS），燃料肿瘤生长，抵抗治疗，并在不同的 站点。在正常结肠中，在活性连续体中存在多个干细胞种群。我们 假设CRC中存在不同的抽动种群，这些不同的抽动种群具有不同的 克隆性特性和肿瘤重塑潜力。使用由LRIG1和LGR5标记的抽动代表 我们将分别使用新颖的单细胞方法来研究 这些人群在理论干预的背景下。首先，我们将确定是否有定义 方向层次结构，储备抽动产生活跃的抽动与相互转换。第二，我们 将确定是否具有恶性特征的抽动是原发性肿瘤中存在的还是TICS获得的 这些从从头开始的特征。第三，我们将确定签名是否得出 来自TIC行为为CRC患者提供预后和/或预测信息。我们的 翻译目标是采用系统方法来预测基于特性的肿瘤复发的可能性 TIC种群的长期目标是使用组合途径改变来靶向TIC行为。