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：脱甲酸调节骨髓中散布肿瘤细胞的休眠状态前列腺癌（PCA）优先转移到骨髓。 Paget的“种子和土壤假说” 1889年被用来描述肿瘤细胞（即种子）转移到骨髓（即土壤）的转移转移性增长的特定因素。最近，一种植物激素的脱甲酸（ABA）调节证明植物种子的休眠和其他胁迫反应在哺乳动物中表达抑制许多细胞类型的增殖。我们的数据表明，ABA影响G0中PCA细胞周期停滞，调节响应化学疗法的PCA存活和ABA受体（LANCL2，PPAR）由DTC表达从人骨髓中恢复。进一步的ABA表达可能代表休眠的常见途径介体（例如TGFß，GAS6，BMP4）。中心假设是：脱甲酸诱导骨髓中转移性DTC的休眠。目标1：确定ABA在骨髓中影响PCA休眠程度的程度。亚物种： 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S 将探讨ABA在建立DTC休眠以及如何调节癌症干细胞（CSC）样的作用活动。体内研究将被检查，利基生产的ABA在维持DTC中的作用休眠。我们将使用从PCA患者的骨髓中分离出的DTC来验证这些观察结果。目标2：确定ABA通过LANCL2或PPAR受体的信号在多大程度上影响 PCA细胞在骨髓中的休眠。亚类假设：ABA与其受体的结合对于 DTC处于休眠状态。方法：在AIM 2A中：我们将定义每个ABA接收器在调节休眠状态，什么是下游信号，在AIM 2B中，我们将确定哪种转录 ABA激活途径以诱导DTC 目标3：定义ABA信号传导在PCA对骨髓化疗的抗性中的作用。亚类假设：休眠的PCA细胞对化学疗法有抵抗力。方法：我们将评估是否 ABA或ABA信号破坏DTC休眠的破坏将通过敏感来改善治疗结果休眠的PCA细胞到当前的化学疗法。