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

摘要：脱落酸对骨髓播散性肿瘤细胞休眠的调节作用 前列腺癌(PCa)优先转移到骨髓。Paget在《种子和土壤假说》中的观点 1889被用来描述肿瘤细胞(即种子)转移到骨髓(即土壤)，这具有 有利于转移性生长的特定因素。近年来，脱落酸(ABA)作为一种植物激素，调节着植物的生长发育。 植物种子的休眠和其他应激反应被证明在哺乳动物中表达，在那里 抑制多种细胞类型的增殖。我们的数据显示，ABA诱导G0中的PCA细胞周期停滞，调节 化疗后前列腺癌生存期和脱落酸受体(LANCL2、PPAR)在DCs中的表达 从人类骨髓中找到的。进一步的ABA表达可能代表了休眠的一条共同途径 中介物(如转化生长因子、Gas6、BMP4)。核心假设是： 脱落酸诱导骨髓中转移的DTCs休眠。 目的1：确定ABA在多大程度上诱导骨髓PCA休眠。子假设： ABA是建立DTC休眠的关键。方法：共培养研究与体内转移模型S 将探索ABA在建立DTC休眠中的作用以及如何调节癌症干细胞(CSC)样 活动。体内研究将检验利基产生的ABA在DTC维持中所起的作用 休眠。我们将用从PCa患者骨髓中分离的DTCs来验证这些观察结果。 目的2：确定ABA信号通过LANCL2或PPAR受体诱导的程度 骨髓中的PCA细胞处于休眠状态。假说：ABA与其受体的结合对 DTC将进入休眠状态。方法：在目标2a中，我们将定义每个ABA受体在 调节休眠和下游信号是什么，在目标2B中，我们将确定什么转录 ABA激活通路诱导DTC 目的3：明确ABA信号在PCa骨髓耐药中的作用。 假说：处于休眠状态的前列腺癌细胞对化疗有抵抗力。方法：我们将评估是否 用ABA或ABA信号破坏DTC休眠将通过敏化改善治疗结果 处于休眠状态的前列腺癌细胞对当前化疗药物的反应。

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.