Role of Twist1 in EMT Maintenance and tumor dormancy

Twist1 在 EMT 维持和肿瘤休眠中的作用

• 批准号: 9113132
• 负责人: David D Tran
• 金额: $ 15.2万
• 依托单位: UNIVERSITY OF FLORIDA
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9113132
• 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; Health; 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; 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; prognostic value; programs; 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（由适用提供）：癌症患者可以在诊断后数十年发展转移性疾病。这种停顿可以通过微转移分布的肿瘤细胞（DTC）休眠来解释，这是癌症进展的一个阶段，其中出现了不对称的残留疾病，但在临床上无法检测到并且对常规化学疗法有抵抗力。癌症休眠的病因以及如何在治疗上解决它的科学家和临床医生。这在很大程度上是由于继承解决此问题的困难， 包括DTC的稀有性和令人惊讶的缺乏肿瘤休眠的遗传模型。尽管在癌症转移的初始阶段隐含了上皮 - 间质转变（EMT），但如何在晚期转移细胞中维持它，以及它是否还调节肿瘤休眠状况尚不清楚。最近，我们详细介绍了EMT与肿瘤休眠之间的机械联系，其中Snail1和Twist1（两个关键EMT诱导的转录因子，彼此合作以启动和维持EMT，以及So Do Twist1可能直接促进肿瘤休眠状态。 Twist1通过诱导的细胞周期停滞和低ERK：p38信号比率维持EMT和可能的肿瘤休眠状态 - 肿瘤休眠的两个关键特征。在人类乳腺癌中观察到Snail1-TWIST1合作，并且发现骨髓DTC中的Twist1：Snail1比率是对遥远复发的高度预测。因此，Twist1代表操纵肿瘤休眠的潜在目标。为了开发安全有效的基于Twist1的应用，Twist1在EMT维护和肿瘤休眠中的作用将需要得到确认和表征。为此，我们建议开发一种EMT维持和肿瘤休眠和基于细胞的系统的小鼠遗传模型，以确定扭曲1诱导的生长停滞的机制：在特定的目标1中，我们利用了MMTV-necunt小鼠乳腺癌的模型，从而发展了ERBBB2阳性乳腺肿瘤。我们已经表明，这种小鼠模型中存在Snail1-TWIST1临时和空间合作，并且存在休眠的DTC，将其确立为人类乳腺癌EMT和休眠的真正遗传模型。为了确认Twist1对于维持肿瘤休眠至关重要，我们将确定扭曲1缺失肿瘤的能力 与对照肿瘤细胞相比，细胞维持休眠的DTC，引起转移和会议治疗耐药性。在特定的目标2中，我们表明细胞因子IL-6是由twist1在晚期EMT中诱导的，并且在Twist1和p38之间是一个重要的中间体。 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.在特定目标3中，我们将收集其他成对的原发性人乳腺肿瘤和BM DTC，以确定BM DTC中Twist1：Snail1比的预测和预后能力与其他生物标志物相比。这三个目标将使我们能够批判性地解决EMT维持和肿瘤休眠中的扭曲1的作用。结果有望提供新的目标来控制肿瘤休眠，并刺激对这个重大问题的研究。