Regulation of Ovarian Cancer Stem Cell Niche by Cancer-Associated Fibroblasts
Abstract
Ovarian cancer is the deadliest of all gynecologic cancers and the fifth leading cause of cancer-related deaths among women in the United States. While most patients respond well initially to the standard of care surgery and chemotherapy, a majority will suffer from disease relapse and will eventually develop chemoresistance. This is one of the main reasons for poor outcome of ovarian cancer patients. Disease relapse is triggered by residual tumors that are enriched in cancer stem cells, a population of cancer cells that are capable of seeding new tumors. Cancer stem cells constitute a small subpopulation in the tumor that are resistant to cytotoxic chemotherapy and, therefore, are a potential cause relapse and chemoresistance. Hence, targeting the cancer stem cells in combination with conventional chemotherapy would be an ideal approach to prevent recurrence. Most studies on cancer stem cells focus on cancer cells alone, while emerging evidence indicate that they exist in a complex microenvironment or niche. The cancer stem cell niche provides critical factors that are essential for the sustenance and growth of cancer stem cells. Poor understanding the reciprocal communications between cancer stem cells and their microenvironment remain a critical barrier to developing effective therapies targeting cancer stem cells to effectively control chemoresistance and relapse. Therefore, there is a need to identify and target the mechanism of reciprocal interactions with the microenvironment that maintains ovarian cancer stem cells and causes disease relapse. We have identified cancer associated fibroblast (CAFs) as a key component of the tumor microenvironment that serve as an ovarian cancer stem cell niche. CAFs are a major constituent of the tumor and promote its growth and spread. It is well known that the residual tumors after neoadjuvant chemotherapy in ovarian cancer patients are enriched in fibroblasts, indicating their possible role in relapse. Recent research has shown that the presence of greater amounts of the non-cancer cells in the tumor microenvironment led to poor outcomes in ovarian cancer patients. Therefore, we studied the role of CAFs in promoting chemoresistance and relapse through providing an optimal environment for the growth of cancer stem cells. Using patient tumor-derived CAFs and 3D culture models mimicking the patient tumors, we have identified the mechanism by which CAFs can support ovarian cancer stem cells. Targeting this mechanism helped sensitize tumors to carboplatin in cell-based experiments and in a mouse model of ovarian cancer. Like cancer cells, CAFs in the tumors are also heterogeneous. We have now identified subpopulations of CAFs and cancer cells that productively talk to each other to maintain cancer stem cells. We propose to characterize these subpopulations and determine the mechanism of the crosstalk between them so that they can be effectively targeted to eliminate disease relapse. The proposed research addresses the FY22 OCRP area of interest, Understand the basic biology and etiology of ovarian cancer initiation, progression, metastasis, recurrence, genetics and other critical events. Studying and targeting ovarian cancer stem cells in isolation is not the most efficient approach, as they exist in a specific microenvironment. Our studies indicate that this microenvironment can reprogram some bulk ovarian cancer cells back into cancer stem cells. Therefore, to effectively prevent relapse, our study will understand and target the crosstalk between the subpopulations of the microenvironment and ovarian cancer cells that maintain the cancer stem cell population. Since a vast majority of ovarian cancer patients suffer from disease relapse and development of chemoresistance, our study has the potential to strongly impact their lives. Therefore, it is very relevant to the vision and mission of OCRP and will positively impact all women with ovarian cancer, includi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310605
Entities
People
- Anirban Mitra
Organizations
- Indiana University
- United States Army