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。研究不同的肿瘤起始细胞 晚期结直肠癌（CRC）的一个主要治疗障碍是治疗后肿瘤复发。这 “癌症干细胞假说”认为，具有干细胞特征的罕见癌细胞群，也 称为肿瘤起始细胞 (TIC)，促进肿瘤生长、抵抗治疗并在远端重新填充肿瘤 网站。在正常结肠中，多个干细胞群以储备-活性连续体的形式存在。我们 假设 CRC 中存在不同的 TIC 群体，并且这些不同的 TIC 群体具有不同的 克隆形成特性和肿瘤增殖潜力。用Lrig1和Lgr5标记的TIC来表示 分别针对储备和活动 TIC，我们将使用新颖的单细胞方法来研究 这些人群处于治疗干预的背景下。首先我们要判断是否有定义 储备 TIC 产生活跃 TIC 与相互转化的定向层次结构。第二，我们 将确定具有恶性特征的 TIC 是否预先存在于原发肿瘤中，或者 TIC 是否获得 这些特征是治疗的结果。第三，我们将判断签名是否派生 TIC 行为的分析可为 CRC 患者提供预后和/或预测信息。我们的 转化目标是应用系统方法根据特性预测肿瘤复发的可能性 TIC 人群的长期目标是使用组合途径改变来针对 TIC 行为。