Project 1: Interrogating Distinct Tumor-Initiating Cells in CRC

项目总结/摘要：P1。询问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。的 “癌症干细胞假说”认为，具有干细胞特征的罕见癌细胞群体， 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，多个干细胞群体以储备-活性连续体存在。我们 假设在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再增殖潜力。使用由Lrig 1和Lgr 5标记的TIC来表示 储备和活跃的TIC，我们将使用新的单细胞方法来研究的行为， 这些人群在治疗干预的背景下。首先，我们将确定是否有一个定义 定向层次结构，其中储备TIC产生活跃TIC，而不是相互转换。二是 将确定具有恶性特征的TIC是否预先存在于原发性肿瘤中，或者TIC是否获得 这些特征是治疗的结果。第三，我们将确定签名是否来自 从TIC行为提供预后和/或预测信息的个人与CRC。我们 翻译目标是应用系统方法来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靶向TIC行为。

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.