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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

基本信息

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
项目类别：
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

项目摘要

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