The Role of Rac1 in Ovarian Cancer Metastasis and Niche Interaction

项目摘要 卵巢癌患者由于晚期诊断和频繁复发而继续具有高死亡率。 卵巢癌并不局限于腹膜腔。扩散和循环的肿瘤细胞是 经常被发现，并与更差的生存结果有关。因此，需要集中努力， 确定允许卵巢癌细胞逃离腹膜的因素，并确定提供安全港的部位 在那里肿瘤细胞可以逃避化疗并被重新激活以引起复发。低数量的 在骨髓中检测到播散性卵巢肿瘤细胞，然而，骨转移的机制 骨髓归巢和移植是未知的。有强有力的证据表明，异常的Rac 1 GT3信号传导 基于作为细胞-细胞粘附调节剂的作用，肌动蛋白有助于肿瘤转移、侵袭和存活， 重组和细胞运动。此外，Rac 1对造血干细胞的植入和静止至关重要。 骨髓龛中的细胞。Wandinger-Ness小组先前报道Rac 1过表达， Rac 1的组成型活性Rac 1b剪接变体在高级别浆液性卵巢肿瘤中升高。 相反，通过围手术期使用Rac 1/Cdc 42双重抑制剂抑制Rac 1，与以下因素相关： 提高患者生存率。总之，数据表明，Rac 1 GTdR可能是一个重要的驱动因素， 卵巢癌扩散，并使植入在一个受保护的利基，如骨髓，从 复发可能起源。本提案将检验Rac 1过表达或过度激活 促进卵巢癌转移，并导致肿瘤细胞扩散到骨髓中， 建立静止的细胞群。通过结合体外细胞分析和异种移植 动物模型研究，Rac 1过表达和抑制对侵袭、转移和骨的影响 将测试骨髓归巢和静止。实验数据将用于参数化 一个计算模型，旨在模拟卵巢癌细胞归巢到骨骼，并确定最关键的 可能作为目标的进程中的节点。总的来说，这些研究将确立Rac 1作为 卵巢癌细胞播散，并验证Rac 1作为高价值的治疗靶点， 减少卵巢癌疾病复发。

PROJECT ABSTRACT Ovarian cancer patients continue to have a high mortality rate due to late stage diagnoses and frequent relapse. Ovarian cancer is not exclusively confined to the peritoneal cavity. Disseminated and circulating tumor cells are often detected and are associated with worse survival outcomes. Therefore, focused efforts are needed to identify factorsthat permit ovarian cancer cells to escape the peritoneum and identify sites that offer safe harbors where the tumor cells can evade chemotherapy and be reactivated to cause relapse. Low numbers of disseminated ovarian tumor cells have been detected in the bone marrow, however, mechanisms for bone marrow homing and engraftment are not known. There is strong evidence that aberrant Rac1 GTPase signaling contributes to tumor metastasis, invasion and survival, based on roles as a regulator of cell-cell adhesion, actin reorganization and cell motility. Furthermore, Rac1 is crucial for engraftment and quiescence of hematopoietic cells in the bone marrow niche. The Wandinger-Ness group previously reported that Rac1 is overexpressed and the constitutively active Rac1b splice variant of Rac1, is elevated in high grade serous ovarian tumors. Conversely, inhibition of Rac1 through perioperative use of a Rac1/Cdc42 dual inhibitor, was associated with improved patient survival. Taken together, the data suggest that Rac1 GTPase may be an important driver in ovarian cancer dissemination and enable engraftment in a protected niche such as the bone marrow from which relapse may originate. The present proposal will test the hypothesis that Rac1 overexpression or hyperactivation promotes ovarian cancer metastasis, and leads to tumor cell dissemination into the bone marrow and establishment of a quiescent, cell population. Through a combination of in vitro cell based assays and xenograft animal model studies, the impact of Rac1 overexpression and inhibition on invasion, metastasis and bone marrow homing and quiescence will be tested. The experimental data will be used to parameterize a computational model designed to simulate ovarian cancer cell homing to the bone and identify the most critical nodes in the process that might serve as targets. Collectively, these studies will establish Rac1 as driver of ovarian cancer cell dissemination and validate Rac1 as a high value therapeutic target with potential impact in reducing ovarian cancer disease relapse.