The control of the breast cancer stem cell state by snail-driven EMT program

 描述(申请人提供)：称为上皮-间充质转化(EMT)的细胞生物学程序在癌症发病机制中起着重要作用。除了EMT计划与肿瘤侵袭和扩散之间的最初联系外，最近发现激活EMT计划可以诱导癌细胞进入癌症干细胞(CSC)状态，从而极大地增强癌细胞在远处转移部位或停止常用抗癌方案后启动肿瘤生长的能力。尽管EMT程序在肿瘤发病机制中具有核心作用，但对体内肿瘤发展过程中被激活的EMT程序的性质，以及随后诱导和/或维持CSC状态的EMT程序的下游介质，人们知之甚少。该项目旨在阐明在以乳腺癌为模型系统的多步骤癌症发病机制中，激活和维持EMT程序的细胞和分子机制以及由此产生的CSC状态。为此，我利用EMT诱导转录因子的基因工程报告鼠系(EMT-TF)，结合优化的本土转移性乳腺肿瘤小鼠模型，确定蜗牛EMT-Tf是乳腺CSC状态的主要决定因素。值得注意的是，Snail对于维持正常的乳腺组织动态平衡是必不可少的，而Snail的耗尽允许选择性地消除乳腺肿瘤干细胞而不是正常的乳腺干细胞。出于这些原因，我建议研究Snail驱动的EMT程序控制乳腺CSC状态的分子机制，并阐明在肿瘤发展过程中首先诱导Snail表达的信号。其目的是(1)确定乳腺CSCs中Snail驱动的EMT程序的下游靶基因，并探讨其预后和治疗价值；(2)研究Snail相互作用的转录辅助因子在CSC状态诱导和维持中的功能；(3)阐明在乳腺肿瘤多步进展过程中Snail激活的细胞自主和非细胞自主信号。

 DESCRIPTION (provided by applicant): The cell-biological program termed epithelial-mesenchymal transition (EMT) plays a prominent role in carcinoma pathogenesis. In addition to the initial connection made between the EMT program and tumor invasion and dissemination, activation of the EMT program was recently found to induce carcinoma cells to enter into the cancer stem cell (CSC) state, thus greatly enhances the abilities of the carcinoma cells to initiate tumor growth at distant metastatic sites or following cessation of common anti-cancer regimen. Despite the central functions of the EMT program in carcinoma pathogenesis, little is known regarding the nature of the EMT program that is activated during tumor development in vivo, nor about the downstream mediators of the EMT program that subsequently induce and/or maintain the CSC state. The proposed project aims to elucidate the cellular and molecular mechanisms that activate and sustain the EMT program and the resulting CSC state during multi-step carcinoma pathogenesis using breast cancer as the model system. To this end, using genetically engineered reporter mouse lines of EMT-inducing transcription factors (EMT-TFs) in combination with an optimized autochthonous mouse model of metastatic mammary tumor, I have identified the Snail EMT- TF as the major determinant of the breast CSC state. Strikingly, Snail is dispensable for maintaining normal tissue homeostasis of the mammary gland, and depletion of Snail allows selective elimination of mammary tumor stem cells over normal mammary stem cells. For these reasons, I propose to investigate the molecular mechanisms underlying the control of breast CSC state by the Snail-driven EMT program, and to elucidate the signals that induce Snail expression at the first place during tumor development. The aims are (1) To identify the downstream target genes of the Snail-driven EMT program in breast CSCs, and to explore their prognostic and therapeutic values; (2) To investigate the functions of Snail-interacting transcription co-factors in induction and maintenance of the CSC state; and (3) To elucidate the cell-autonomous and non-cell autonomous signals responsible for Snail-activation during multi-step mammary tumor progression.