ROLE OF TWIST1 IN EMT MAINTENANCE AND TUMOR DORMANCY

TIST1 在 EMT 维持和肿瘤休眠中的作用

• 批准号: 8706827
• 负责人: David D Tran
• 金额: $ 15.2万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8706827
• 关键词: Address; Biological Markers; Bone Marrow; Breast; Cancer Etiology; Cancer Patient; Cell Cycle Arrest; Cells; Clinical; Cytokine Network Pathway; Data; Diagnosis; Disease; Disease-Free Survival; Distant; Epithelial; Epithelial Cells; Genetic Models; Growth; Human; Interleukin-6; Link; Localized Malignant Neoplasm; MAPK14 gene; Maintenance; Malignant Neoplasms; Mammary Neoplasms; Mesenchymal; Modeling; Molecular; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Patients; Play; Predictive Value; Primary Neoplasm; Proliferating; Recurrence; Relapse; Research; Residual Tumors; Resistance; Role; Scientist; Signal Pathway; Signal Transduction; Staging; Stem cells; System; TWIST1 gene; Testing; Time; Transcription Repressor/Corepressor; autocrine; base; cancer cell; chemotherapy; cytokine; genetic regulatory protein; in vivo; malignant breast neoplasm; mouse model; neoplastic cell; overexpression; paracrine; prevent; prognostic; programs; public health relevance; transcription factor; tumor; tumor progression

DESCRIPTION (provided by applicant): Cancer patients can develop metastatic disease years to decades after diagnosis. This pause can be explained by micrometastatic disseminated tumor cell (DTC) dormancy, a stage in cancer progression in which asymptomatic residual disease is present but clinically undetectable and resistant to conventional chemotherapy. The etiology of cancer dormancy and how to therapeutically address it have confounded scientists and clinicians. This is due in large part to the inherent difficulties in approaching this problem, including the rarity of DTCs and the surprising lack of genetic models of tumor dormancy. Although the Epithelial-Mesenchymal Transition (EMT) has been implicated in the initial stages of cancer metastasis, how it is maintained in late metastatic cells and whether it also regulates tumor dormancy remains unclear. We have recently detailed a mechanistic link between EMT and tumor dormancy in which Snail1 and Twist1, two key EMT-inducing transcription factors, cooperate with each other to initiate and maintain EMT, respectively, and in so doing Twist1 may contribute directly to tumor dormancy. Twist1 maintains EMT and perhaps tumor dormancy by inducing cell cycle arrest and a low ERK:p38 signaling ratio - two key features of tumor dormancy. The Snail1-Twist1 cooperation was observed in human breast cancer and the Twist1:Snail1 ratio in bone marrow DTCs was found to be highly predictive of distant relapses. Therefore, Twist1 represents a potential target to manipulate tumor dormancy for clinical benefits. To develop safe and effective Twist1-based applications, Twist1's role in EMT maintenance and tumor dormancy will need to be confirmed and characterized. To that end, we propose to develop a mouse genetic model of EMT maintenance and tumor dormancy and a cell-based system to determine the mechanism of Twist1-induced growth arrest: In specific aim 1, we take advantage of the MMTV-NeuNT mouse model of breast cancer which develops ErbB2- positive breast tumors de novo. We have shown that the Snail1-Twist1 temporal and spatial cooperation exists and dormant DTCs are present in this mouse model, establishing it as a bona fide genetic model of human breast cancer EMT and dormancy. To confirm that Twist1 is critical for maintaining tumor dormancy, we will determine the ability of Twist1- depleted tumor cells to maintain dormant DTCs, give rise to metastases, and confer treatment resistance as compared to control tumor cells. In specific aim 2, we have shown that the cytokine IL-6 is induced by Twist1 in late EMT and an important intermediary between Twist1 and p38. Using transient TGF¿1-treated epithelial cells and MMTV-NeuNT mice, we will determine how Twist1 induces IL-6, whether IL-6 is critical for Twist1-dependent EMT maintenance and tumor dormancy in vivo, and whether other cytokines or regulatory proteins are involved in Twist1-associated autocrine and paracrine cytokine network. In specific aim 3, we will collect additional paired primary human breast tumors and BM DTCs to determine the predictive and prognostic power of the Twist1:Snail1 ratio in BM DTCs as compared to other biomarkers. These 3 aims will allow us to critically address a role for Twist1 in EMT maintenance and tumor dormancy. The result will hopefully provide new targets to control tumor dormancy and stimulate research into this significant problem.

描述(由申请人提供)：癌症患者在确诊后数年至数十年可发展为转移性疾病。这种暂停可以用微转移播散性肿瘤细胞(DTC)休眠来解释，DTC是癌症进展中的一个阶段，在这个阶段，虽然存在无症状的残留病，但临床上无法检测到，并且对传统化疗具有耐药性。癌症休眠的病因以及如何从治疗上解决它，让科学家和临床医生感到困惑。这在很大程度上是由于处理这一问题的内在困难， 包括DTC的稀有，以及令人惊讶的缺乏肿瘤休眠的遗传模型。尽管上皮-间充质转化(EMT)与肿瘤转移的早期阶段有关，但它是如何在晚期转移细胞中维持的，以及它是否也调节了肿瘤的休眠尚不清楚。我们最近详细描述了EMT和肿瘤休眠之间的机制联系，其中两个关键的EMT诱导转录因子Snail1和Twist1相互合作，分别启动和维持EMT，在这样做的过程中，Twist1可能直接导致肿瘤休眠。Twist1通过诱导细胞周期停滞和低ERK：p38信号比率来维持EMT，甚至可能是肿瘤休眠--这是肿瘤休眠的两个关键特征。在人类乳腺癌中观察到了Snail1-Twist1的协同作用，骨髓DCs中的Twist1：Snail1比率被发现对远处复发有很高的预测作用。因此，Twist1代表了一个潜在的靶点，可以操纵肿瘤的休眠状态以获得临床益处。为了开发安全和有效的基于Twist1的应用，Twist1的S在EMT维持和肿瘤休眠中的作用将需要得到证实和表征。为此，我们建议建立一个EMT维持和肿瘤休眠的小鼠遗传学模型和一个基于细胞的系统来确定Twist1诱导的生长停滞的机制：在特定的目标1，我们利用MMTV-NeuNT小鼠乳腺癌模型，它在新生的情况下发展为ErbB2阳性的乳腺癌。我们已经证明了Snail1-Twist1在时间和空间上的协同作用，并且在这个小鼠模型中存在休眠的DTCs，建立了一个真正的人类乳腺癌EMT和休眠的遗传模型。为了确认Twist1对维持肿瘤休眠至关重要，我们将确定Twist1缺失的肿瘤的能力 与对照肿瘤细胞相比，细胞维持休眠的DTCs，引起转移，并产生治疗耐药性。在特定的目标2中，我们已经证明了细胞因子IL-6是由Twist1在EMT晚期诱导的，并且是Twist1和p38之间的重要中介。利用瞬时转化生长因子1处理的上皮细胞和MMTV-NeuNT小鼠，我们将确定Twist1如何诱导IL-6，IL-6是否在体内Twist1依赖的EMT维持和肿瘤休眠中起关键作用，以及是否有其他细胞因子或调节蛋白参与Twist1相关的自分泌和旁分泌细胞因子网络。在具体目标3中，我们将收集更多配对的原发人类乳腺肿瘤和BM DTC，以确定与其他生物标记物相比，BM DTC中Twist1：Snail1比率的预测和预后能力。这三个目标将使我们能够批判性地解决Twist1在EMT维持和肿瘤休眠中的作用。这一结果有望为控制肿瘤休眠提供新的靶点，并推动对这一重大问题的研究。