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: 10382130
• 负责人: Melanie R Haluska
• 金额: $ 0.75万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382130
• 关键词: Actins; Address; Adhesions; Animal Model; Biological Assay; Blood Circulation; Bone Marrow; Cancer Patient; Career Mobility; Cell Culture Techniques; Cell model; Cell-Cell Adhesion; Cells; Computer Models; Computing Methodologies; Data; Development; Diagnosis; Distant; Distant Metastasis; Engraftment; Fellowship; Greater sac of peritoneum; Guanosine Triphosphate Phosphohydrolases; Hematopoietic; Homing; In Vitro; Interview; Malignant neoplasm of ovary; Manuscripts; Metastatic Neoplasm to the Liver; Modeling; Neoplasm Circulating Cells; Neoplasm Metastasis; Oral; Ovarian; Ovarian Serous Tumor; Patients; Perioperative; Peritoneum; Population; Process; Publications; RNA Splicing; Readiness; Recurrent disease; Relapse; Reporting; Role; Schedule; Signal Transduction; Site; Study models; Testing; Time; Translational Research; Tumor Burden; Tumor Tissue; Update; Validation; Variant; Woman; Work; Xenograft procedure; base; bone; cancer cell; cell motility; chemotherapy; experimental analysis; graduate student; improved; inhibitor/antagonist; knock-down; meetings; model design; mortality; neoplastic cell; new therapeutic target; ovarian neoplasm; overexpression; predictive modeling; repository; stable cell line; survival outcome; therapeutic target; tumor; tumor growth

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.

项目摘要 由于晚期诊断和频繁复发，卵巢癌患者的死亡率仍然很高。 卵巢癌不仅限于腹膜腔。传播和循环的肿瘤细胞是 通常被检测到，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脱腹膜并识别提供安全港口的地点的因素 肿瘤细胞可以逃避化疗并重新激活以引起复发。低数量 然而，在骨髓中已经检测到散布的卵巢肿瘤细胞，骨骼的机制 骨髓归巢和植入尚不清楚。有充分的证据表明异常Rac1 GTPase信号传导 基于细胞粘附的调节剂的作用，有助于肿瘤转移，侵袭和生存 重组和细胞运动。此外，Rac1对于造血的植入和静止至关重要 骨髓小裂中的细胞。 Wandinger-ness组以前报道Rac1过表达，并且 Rac1的组成型Rac1b剪接变体在高级浆液卵巢肿瘤中升高。 相反，通过围手术期使用RAC1/CDC42双重抑制剂对Rac1的抑制作用与 改善了患者的生存。综上所述，数据表明Rac1 GTPase可能是重要的驱动力 卵巢癌的传播并使受保护小众的植入（例如骨髓） 复发可能起源。本提案将检验Rac1过表达或过度激活的假设 促进卵巢癌转移，并导致肿瘤细胞传播到骨髓和 建立静止的细胞种群。通过基于体外细胞的测定和异种移植的组合 动物模型研究，Rac1过表达和抑制对侵袭，转移和骨骼的影响 将测试骨髓归巢和静止。实验数据将用于参数化 计算模型旨在模拟卵巢癌细胞向骨骼的归巢并确定最关键的 在过程中可能用作目标的节点。总的来说，这些研究将建立Rac1作为 卵巢癌细胞的传播和验证Rac1是一个高价值治疗靶标，潜在影响 减少卵巢癌疾病复发。