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

摘要：脱落酸调节骨髓中播散性肿瘤细胞的休眠 前列腺癌（PCa）优先转移到骨髓。佩吉特的“种子和土壤假说”， 1889已经被用于描述肿瘤细胞（即种子）转移到骨髓（即土壤），其具有 有助于转移性生长的特定因素。最近，脱落酸（阿坝），一种植物激素，调节 植物种子休眠和其他应激反应被证明在哺乳动物中表达， 抑制多种细胞类型的增殖。我们的数据表明，阿坝诱导PCa细胞周期阻滞在G0期，调节 PCa对化疗的存活率，以及DTC表达阿坝受体（LANCL 2，PPAR γ） 从人类骨髓中提取的阿坝的进一步表达可能代表了休眠的共同途径 介质（例如TGF β、GAS 6、BMP 4）。核心假设是： 脱落酸诱导骨髓中转移性DTC休眠。 目的1：确定阿坝诱导骨髓中PCa休眠的程度。次假设： 阿坝是建立DTC休眠的关键。方法：共培养研究和体内转移模型 将探讨阿坝在建立DTC休眠中的作用以及如何调节癌症干细胞（CSC）样 活动在体内研究中，将检查小生境产生的阿坝在DTC维持中的作用 休眠我们将用从PCa患者骨髓中分离的DTC验证这些观察结果。 目的2：确定阿坝信号通过LANCL 2或PPAR γ受体诱导的程度。 骨髓中PCa细胞的休眠。亚假设：阿坝与其受体的结合对于 DTC将休眠。方法：在目标2A中：我们将定义每个阿坝受体在 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 阿坝可激活这些通路，诱导DTC 目的3：明确骨髓中阿坝信号在前列腺癌化疗耐药中的作用。 亚假设：Doradian PCa细胞对化疗耐药。方法：我们将评估 通过阿坝或阿坝信号传导破坏DTC休眠将通过敏化 休眠的前列腺癌细胞对目前的化疗。

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.