Microenvironment-Regulated microRNAs Promote Ovarian Cancer Metastatic Colonization
Abstract
The spreading of cancer cells from the primary ovarian tumor to distant organs within the abdomen is responsible for most ovarian cancer-related deaths. Yet it remains the least understood aspect of the disease. During this process, the cancer cells floating in ascites attach to various organs within the abdominal cavity and colonize them to form metastasis. A better understanding of the regulation of this key step is needed in order to develop novel and effective therapies. Using unique experimental models that replicate closely the early steps of metastatic colony formation in patients, we have identified key regulatory molecules called microRNAs that regulate metastasis. We have found that the patient s own normal cells at the metastatic site contribute to the control expression of these microRNAs in the invading ovarian cancer cells and thereby promote metastasis. In the current proposal, we aim to identify the mechanisms by which expression of these microRNAs in ovarian cancer cells is regulated by the microenvironment at the site of metastasis. We also plan to study how the microRNAs contribute to formation of metastatic tumors by regulating multiple proteins in the ovarian cancer cells. The knowledge thus gained by experiments proposed in this grant proposal will enhance our understanding of the complicated process of metastasis. Moreover, the findings will have the potential to lead to novel therapies that target critical steps in metastasis and improve treatment outcomes for patients with ovarian cancer. My long-term research goal is to understand how the reciprocal interactions between ovarian cancer cells and the microenvironment regulate metastatic colonization and to use this information to help ovarian cancer patients. The proposed research will result in important publications, which will move the field forward and form the basis for subsequent federal grant applications. This will result in my recognition among peers, establish me as a successful ovarian cancer researcher, and help me develop fruitful collaborations that will pool my strengths with those of others in the field and strengthen us in our fight against ovarian cancer. It will also help me realize my dream to eventually translate my findings into the development of more effective therapies for ovarian cancer. At the time of diagnosis, 70% of ovarian cancer patients present with metastatic disease. It is therefore absolutely essential to develop therapies that target metastasis. However, our present knowledge of the process is limited. Therefore, we must strive towards understanding the process of metastasis. The present proposal attempts to find out how the cancer cells interact with the normal tissue during metastasis and how this triggers specific regulators in the cancer cells to help them successfully metastasize. Armed with this knowledge, we can embark upon the development of new therapies that prevent the successful interactions of the cancer cells with the normal tissue. Alternately, we can block the regulators in the cancer cells to prevent metastasis. This will potentially benefit the majority of the ovarian cancer patients and provide a boost to the field, which has not seen any major improvement in treatment outcome over the last 30 years. In the short term, this study will open up the field to the phenomenon of regulation of key microRNAs in cancer cells by the normal tissues during metastasis. This will attract many other researchers to study this hitherto unexplored subject and lead to better understanding of a critical step in metastasis in ovarian cancer as well as in other cancers. The long-term contribution of the proposed research is the development of novel therapies targeting the key regulators of ovarian cancer metastasis. Such approaches would potentially improve therapeutic outcomes of ovarian cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510253
Entities
People
- Anirban Mitra
Organizations
- Indiana University
- United States Army