Project 2: Abscisic Acid Regulates Dormancy of Disseminated Tumor Cells in Bone Marrow

项目2：脱落酸调节骨髓中播散性肿瘤细胞的休眠

基本信息

批准号：
10427245
负责人：
RUSSELL S TAICHMAN
金额：
$ 15.51万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-05 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10427245
关键词：
Abscisic Acid Adjuvant Adjuvant Therapy Aftercare Agonist Aspirate substance BMP4 Binding Biology Bone Marrow Cancer Patient Cell Count Cell Cycle Cell Cycle Arrest Cells Coculture Techniques Data Disease Genetic Transcription Growth Human Immune Knowledge Link Maintenance Malignant neoplasm of prostate Mammalian Cell Mammals Marrow Mediator of activation protein Mesenchymal Stem Cells Metastatic Neoplasm to the Bone Metastatic to Modeling Molecular Neoplasm Metastasis Pathway interactions Peroxisome Proliferator-Activated Receptors Plant Growth Regulators Plants Play Proliferating Receptor Signaling Recurrence Relapse Resistance Role Seeds Signal Transduction Soil System Testing Therapeutic Transforming Growth Factor beta Treatment outcome antagonist biological adaptation to stress bone cancer stem cell cancer survival cell growth cell type chemotherapeutic agent chemotherapy effective therapy hematopoietic stem cell niche human disease human model improved in vivo knock-down neoplastic cell prevent prostate cancer cell prostate cancer cell line receptor response stem-like cell targeted agent therapeutic target tumor tumor growth

项目摘要

Abstract: Abscisic Acid Regulates Dormancy of Disseminated Tumor Cells in Bone Marrow Prostate cancer (PCa) preferentially metastasizes to the bone marrow. Paget's “seed and soil hypothesis” in 1889 has been used to describe tumor cells (i.e. seed) metastasize to bone marrow (i.e. soil), which have specific factors conducive to metastatic growth. Recently, abscisic acid (ABA), a phytohormone, regulates the dormancy of plant seeds and other stress responses was demonstrated to be expressed in mammals where it inhibits proliferation of many cell types. Our data shows that ABA induces PCa cell cycle arrest in G0, regulates PCa survival in response to chemotherapy, and ABA receptors (LANCL2, PPAR) are expressed by DTCs recovered from human marrow. Further ABA expression may represent a common pathway for dormancy mediators (e.g. TGFß, GAS6, BMP4). The central hypothesis is: Abscisic acid induces dormancy of metastatic DTCs in the bone marrow. Aim 1: Determine the extent to which ABA induces PCa dormancy in bone marrow. Subhypothesis: ABA is critical for establishing DTC dormancy. Approach: Coculture studies and in vivo metastasis model s will explore the role of ABA in establishing DTC dormancy and how regulates cancer stem cell (CSC)-like activities. In vivo studies will be examine the role that niche-produced ABA plays in the maintenance of DTC dormancy. We will validate these observations with DTCs isolated from marrow of PCa patients. Aim 2: Determine the extent to which ABA signaling through LANCL2 or PPAR receptors induces dormancy of PCa cells in the marrow. Subhypothesis: The binding of ABA to its receptors are critical for DTCs to become dormant. Approach: In Aim 2A: we will defined the role that each ABA receptor plays in regulating dormancy and what are the downstream signals, and in Aim 2B, we will determine what transcription pathways are activated by ABA to induce DTC Aim 3: Define the role of ABA signaling in resistance of PCa to chemotherapy in bone marrow. Subhypothesis: Dormant PCa cells are resistant to chemotherapy. Approach: We will to evaluate whether the disruption of DTC dormancy by ABA or ABA signaling will improve treatment outcomes by sensitizing dormant PCa cells to current chemotherapies.

摘要：脱落酸调节骨髓中播散性肿瘤细胞的休眠佩吉特提出的“种子和土壤假说”表明，前列腺癌（PCa）优先转移至骨髓。第1889章被用来描述肿瘤细胞（即种子）转移到骨髓（即土壤），最近，脱落酸（ABA），一种植物激素，调节着转移生长。植物种子和其他宿舍应激反应的机制已被证明在哺乳动物中表达我们的数据表明，ABA 会诱导 PCa 细胞周期停滞在 G0 期，并调节细胞周期。 PCa 因化疗而存活，DTC 表达 ABA 受体（LANCL2、PPAR）从人类骨髓中恢复的 ABA 表达可能代表了休眠的共同途径。介体（例如 TGFß、GAS6、BMP4）。中心假设是：脱落酸诱导骨髓中转移性 DTC 的休眠。目标 1：确定 ABA 在骨髓中诱导 PCa 休眠的程度。 ABA 对于建立 DTC 休眠至关重要。方法：共培养研究和体内转移模型。将探讨 ABA 在建立 DTC 休眠中的作用以及如何调节类癌症干细胞 (CSC) 体内研究将检查生态位产生的 ABA 在维持 DTC 中所起的作用。我们将用从 PCa 患者骨髓中分离出的 DTC 来验证这些观察结果。目标 2：确定 ABA 信号通过 LANCL2 或 PPARα 受体诱导的程度子假设：ABA 与其受体的结合对于方法：在目标 2A 中，我们将定义每个 ABA 受体在其中发挥的作用。调节以及下游宿舍信号是什么，在目标 2B 中，我们将确定什么转录 ABA 激活途径诱导 DTC 目标 3：明确 ABA 信号传导在骨髓 PCa 化疗耐药中的作用。子假设：休眠的 PCa 细胞对化疗有抵抗力。方法：我们将评估是否存在化疗耐药性。通过 ABA 或 ABA 信号传导破坏 DTC 休眠将通过敏化改善治疗结果休眠的 PCa 细胞接受当前的化疗。