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: 8442515
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442515
• 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）：癌症患者可在诊断后数年至数十年发生转移性疾病。这种停顿可以用微转移性播散性肿瘤细胞（DTC）休眠来解释，这是癌症进展的一个阶段，其中存在无症状的残留疾病，但临床上无法检测到，并且对常规化疗具有抗性。癌症休眠的病因学以及如何治疗它使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固有困难， 包括DTC的罕见性和令人惊讶的肿瘤休眠遗传模型的缺乏。尽管上皮-间充质转化（EMT）与癌症转移的初始阶段有关，但它如何在晚期转移细胞中维持以及它是否也调节肿瘤休眠仍不清楚。我们最近详细介绍了EMT和肿瘤休眠之间的机制联系，其中Snail 1和Twist 1，两个关键的EMT诱导转录因子，相互合作，启动和维持EMT，分别，这样做Twist 1可能直接有助于肿瘤休眠。Twist 1通过诱导细胞周期停滞和低ERK：p38信号传导比率（肿瘤休眠的两个关键特征）来维持EMT和可能的肿瘤休眠。在人类乳腺癌中观察到Snail 1-Twist 1合作，并且发现骨髓DTC中的Twist 1：Snail 1比率高度预测远处复发。因此，Twist 1代表了操纵肿瘤休眠以获得临床益处的潜在靶点。 为了开发安全有效的基于Twist 1的应用，Twist 1在EMT维持和肿瘤休眠中的作用需要得到证实和表征。为此，我们建议开发EMT维持和肿瘤休眠的小鼠遗传模型和基于细胞的系统以确定Twist 1诱导的生长停滞的机制：在具体目标1中，我们利用乳腺癌的MMTV-NeuNT小鼠模型，其从头发展ErbB 2阳性乳腺肿瘤。我们已经证明Snail 1-Twist 1时空合作存在，并且该小鼠模型中存在休眠的DTCs，将其建立为人类乳腺癌EMT和休眠的真正遗传模型。为了证实Twist 1对于维持肿瘤休眠是至关重要的，我们将确定Twist 1缺失的肿瘤细胞的能力。 与对照肿瘤细胞相比，细胞维持休眠的DTC，引起转移，并赋予治疗抗性。在具体目标2中，我们已经表明，细胞因子IL-6是由Twist 1诱导的晚期EMT和Twist 1和p38之间的重要中介。使用瞬时TGF？1处理的上皮细胞和MMTV-NeuNT小鼠，我们将确定Twist 1如何诱导IL-6，IL-6是否对Twist 1依赖的EMT维持和体内肿瘤休眠至关重要，以及其他细胞因子或调节蛋白是否参与Twist 1相关的自分泌和旁分泌细胞因子网络。在具体目标3中，我们将收集额外配对的原发性人乳腺肿瘤和BM DTC，以确定与其他生物标志物相比，BM DTC中Twist 1：Snail 1比值的预测和预后能力。 这三个目标将使我们能够关键地解决Twist 1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，并促进对这一重大问题的研究。