The Role of Rac1 in Ovarian Cancer Metastasis and Niche Interaction

Rac1 在卵巢癌转移和生态位相互作用中的作用

• 批准号: 9755762
• 负责人: Melanie R Haluska
• 金额: $ 3.4万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755762
• 关键词: Actins; Animal Model; Biological Assay; Blood; Blood Circulation; Bone Marrow; CXCR4 gene; Cancer Patient; Cancer cell line; Cell Line; Cell-Cell Adhesion; Cells; Computer Simulation; Computing Methodologies; Data; Diagnosis; Disease Outcome; Engraftment; Extravasation; Goals; Greater sac of peritoneum; Growth; Guanosine Triphosphate Phosphohydrolases; Hematopoietic; Hematopoietic stem cells; Homing; In Vitro; Intraperitoneal Injections; Knock-out; Malignant neoplasm of ovary; Measures; Mediating; Modeling; Neoplasm Circulating Cells; Neoplasm Metastasis; Omentum; Ovarian Serous Adenocarcinoma; Ovarian Serous Tumor; Patients; Perioperative; Peritoneal; Peritoneum; Population; Process; Property; RNA Splicing; Recurrent disease; Relapse; Reporting; Role; Series; Signal Transduction; Site; Stream; Study models; Testing; Therapeutic Intervention; Tumor Burden; Variant; Woman; Xenograft procedure; base; bone; cancer cell; cell growth; cell motility; chemotherapy; epithelial to mesenchymal transition; improved; in vivo; inhibitor/antagonist; insight; knock-down; model design; mortality; neoplastic cell; new therapeutic target; ovarian neoplasm; overexpression; stem; survival outcome; therapeutic target; tool; tumor

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.

项目摘要 由于诊断晚期和频繁复发，卵巢癌患者的死亡率仍然很高。 卵巢癌不仅仅局限于腹膜腔。播散性和循环性肿瘤细胞是 经常被发现并与较差的生存结果相关。因此，需要集中精力 确定允许卵巢癌细胞逃逸腹膜的因素并确定提供安全港的位点 肿瘤细胞可以逃避化疗并被重新激活以导致复发。数量少 已在骨髓中检测到播散性卵巢肿瘤细胞，然而，骨的机制 骨髓归巢和植入尚不清楚。有强有力的证据表明 Rac1 GTPase 信号传导异常 基于细胞间粘附、肌动蛋白的调节作用，有助于肿瘤转移、侵袭和存活 重组和细胞运动。此外，Rac1 对于造血细胞的植入和静止至关重要。 骨髓微环境中的细胞。 Wandinger-Ness 小组之前报道过 Rac1 过度表达并且 Rac1 的组成型活性 Rac1b 剪接变体在高级浆液性卵巢肿瘤中升高。 相反，通过围手术期使用 Rac1/Cdc42 双重抑制剂抑制 Rac1 与 提高患者的生存率。综上所述，数据表明 Rac1 GTPase 可能是一个重要的驱动因素 卵巢癌传播并能够在受保护的环境中植入，例如骨髓 可能会复发。目前的提案将检验 Rac1 过度表达或过度激活的假设 促进卵巢癌转移，并导致肿瘤细胞播散到骨髓中 建立静止的细胞群。通过体外细胞分析和异种移植相结合 动物模型研究，Rac1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 旨在模拟卵巢癌细胞归巢到骨骼并识别最关键的计算模型 流程中可能充当目标的节点。总的来说，这些研究将确定 Rac1 作为 卵巢癌细胞传播并验证 Rac1 作为高价值治疗靶点，具有潜在影响 减少卵巢癌疾病的复发。