An Inducible Model for Studying Cancer Stem Cells in PDAC

项目摘要 40多年来首次提出的癌症干细胞(CSC)理论 之前，他指出，一小部分癌细胞具有与 正常干细胞，如自我更新和多谱系分化的能力，是 肿瘤异质性、进展和耐药性的主要驱动因素。然而，已经有了 关于CSC的起源、身份和功能的持续争议，很大程度上是由于 缺乏强有力的和生理的方法来具体识别、跟踪和瞄准 在完整的肿瘤中罕见的CSC群体。为了填补这一空白，我们开发了一种新的诱导器 胰腺导管腺癌基因工程小鼠模型(GEMM)， 这使我们能够进行体内血统追踪，消融，以及体外分析 CSC来自自体PDAC肿瘤的壁龛。使用这个强大的新系统，我们的提案 将研究(1)在PDAC进展和复发期间CSC生态位的动态，(2) 前述推定的PDAC“CSC”标记的性能，以及(3)功能性 CSC生态位在PDAC侵袭、转移和化疗耐药中的意义

Project Summary The Cancer Stem Cell (CSC) theory, which was first proposed more than four decades ago, states that a small population of cancer cells possess the characteristics associated with normal stem cells such as the capacities for self-renewal and multi-lineage differentiation, is the primary driver of tumor heterogeneity, progression, and resistance. However, there have been on-going controversies regarding the origins, identities and functions of CSCs, in large part due to the lack of vigorous and physiological approaches to specifically identify, track, and target the rare CSC population in intact tumors. To fill this gap, we have developed a new inducible genetically engineered mouse model (GEMM) of Pancreatic ductal adenocarcinoma (PDAC), which enable us to conduct in vivo lineage tracing, ablation, as well as ex vivo analysis of the CSC niches from autochthonous PDAC tumors. Using this powerful new system, our proposal will examine (1) the dynamics of the CSC niches during PDAC progression and relapse, (2) the performance of previously described putative PDAC “CSC” markers, and (3) the functional significance of the CSC niches to PDAC invasion, metastasis and chemo-resistance.