Pleiotropic functions of FOXC2 in EMT, stem cells and breast cancer progression

对治疗产生抵抗力、肿瘤复发和转移是乳腺癌的重大风险。 并对这些癌症患者中的大多数死亡负责。最近的研究表明 证明了发育过程被称为上皮-间充质-转化(EMT)以及 在这些不同的过程中，一种称为癌症干细胞(CSC)的癌细胞亚群。我们和其他人 已经表明EMT计划和干细胞特性是相互关联的，特别是癌细胞 能够通过激活EMT获得干细胞属性。这表明，以EMT为目标 该计划可能会减轻疾病负担，并将减少癌症患者的死亡。然而，稀缺 从肿瘤微环境发出的能够诱导EMT的信号通路-包括 炎性细胞因子和转化生长因子β-1(转化生长因子β-1)使其不能作为治疗靶点 急诊室。在过去的9年里，我们实验室的累积研究已经导致了对 转录因子FOXC2在肿瘤转移中起关键作用，也是肿瘤常见的下游效应因子。 多个EMT信号通路，对于CSC物业的采购是不可或缺的。一个特点 CSCs的特点是能够通过不对称或对称的自我更新类型的细胞分裂进行自我更新 从而使CSC池得以继续存在和扩展。目前的提案将 系统测试FOXC2作为促进CSC自我更新的分子开关的关键元件的作用 和扩增，并研究FOXC2的异常激活是否通过Notch导致CSC数量增加 信号，导致肿瘤进展和转移。我们将使用体外和体内肿瘤的组合 模型、患者来源的异种移植以及基因工程小鼠模型来梳理这一点 进程。我们还将研究转化生长因子β1，一个生理上相关的EMT的诱导者，在口述中的功能。 FOXC2诱导的CSC扩张。此外，我们还将评估FOXC2调节的有丝分裂书签在维持 干细胞分裂后CSCs的身份。最后，我们将测试精选的小分子抑制剂 调制FOXC2-在EMT期间选择性防止CSC扩张的作用。意义：总而言之， 我们的建议不仅有助于澄清规范CSC自我续订和扩张的基本流程 在EMT期间的CSC，但也将有助于设计新的战略，从而提供转变的机会 CSC向更多分化细胞和耐排气治疗、易转移的CSCs的平衡。

Development of resistance to therapies, tumor relapse, and metastasis pose significant risks to breast cancer patients and are responsible for the majority deaths among these cancer patients. Recent studies have demonstrated that the developmental process is known as epithelial-mesenchymal-transition (EMT) as well as a subpopulation of cancer cells termed cancer stem cells (CSC), in these various processes. We and others have shown that the EMT program and stem cell properties are interconnected, and specifically, cancer cells are capable of acquiring stem cell attributes through the activation of EMT. This suggested that targeting EMT program may reduce the disease burden and will decrease death among cancer patients. However, the dearth of signaling pathways emanating from the tumor microenvironment capable of inducing EMT - including inflammatory cytokines and transforming growth factor β-1 (TGFβ1) makes it impossible to therapeutically target EMT. Cumulative studies from our laboratory over the last 9 years have resulted in the seminal identification of the transcription factor FOXC2, as a key player in metastasis and also as a common downstream effector of multiple EMT-signaling pathways and indispensable for the procurement of CSC properties. A characteristic feature of CSCs is their capability to self-renew via asymmetrical or symmetrical self-renewal type of cell divisions thereby enabling the continued existence and expansion of the CSC pool. The current proposal will systematically test the role of FOXC2 as a critical element of the molecular switch facilitating CSC self-renewal and expansion, and investigate if aberrant activation of FOXC2 leads to increase in CSC populations via Notch signaling, resulting in tumor progression and metastasis. We will use a combination of in vitro-, and in vivo tumor models, and patient-derived xenografts as well as genetically engineered mouse models to tease out this process. We will also examine the function of TGFβ1, a physiologically relevant inducer of EMT, in dictating FOXC2-induced CSC expansion. Also, we will evaluate FOXC2-regulated mitotic bookmarking in maintaining the identity of the CSCs following stem cell division. Finally, we will test select small molecule inhibitors capable of modulating FOXC2-function in selectively preventing CSC expansion during EMT. Significance: In summary, our proposal will not only help clarify the fundamental processes regulating CSC self-renewal and expansion of CSCs during EMT but will also contribute to designing novel strategies that would provide an opportunity to shift the balance of CSC towards more differentiated cells and exhaust therapy-resistant, metastasis-prone CSCs.