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，死亡率仍然很高。 卵巢癌并不局限于腹膜腔。播散性和循环性肿瘤细胞 经常被发现，并与较差的生存结果相关。因此，需要有重点的努力来 确定允许卵巢癌细胞逃出腹膜的因素，并确定提供安全避难所的位置 在这种情况下，肿瘤细胞可以逃避化疗并被重新激活以导致复发。数量较少 已经在骨髓中检测到播散性卵巢肿瘤细胞，然而，骨骼的机制 骨髓归巢和植入尚不清楚。有强有力的证据表明，异常的rac1 GTPase信号 作为细胞间黏附的调节因子，肌动蛋白参与肿瘤的转移、侵袭和生存。 重组和细胞运动。此外，rac1对造血细胞的植入和静止起着至关重要的作用。 骨髓壁龛中的细胞。Wandinger-Ness研究小组此前曾报道，rac1基因过度表达， 在高级别浆液性卵巢肿瘤中，具有构成活性的rac1b剪接变异体在卵巢浆液性肿瘤中升高。 相反，通过围手术期使用rac1/cd42双重抑制剂抑制rac1与 提高了患者的存活率。综上所述，这些数据表明，rac1 GTP酶可能是 卵巢癌的扩散和能够在受保护的利基环境中植入，例如来自 复发可能源于复发。目前的提议将检验这样的假设，即rac1过度表达或过度激活 促进卵巢癌转移，并导致肿瘤细胞扩散到骨髓和 建立一个静止的细胞群体。通过体外细胞检测和异种移植相结合 Rac1过表达和抑制对侵袭、转移和骨的影响的动物模型研究 将测试骨髓归巢和静止状态。实验数据将被用来对一个 旨在模拟卵巢癌细胞归巢到骨骼并确定最关键的 进程中可能充当目标的节点。总而言之，这些研究将确定rac1是 卵巢癌细胞转移和验证rac1作为一个高价值的治疗靶点的潜在影响 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 factors that 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.