ARID3B Induces CD133-Mediated Homing to the Ovarian Cancer Metastatic Niche
Abstract
Epithelial ovarian cancer is the fifth leading cause of cancer death in women in the United States. Importantly, over 70% of woman with ovarian cancer will not survive beyond 5 years of diagnosis. The vast majority of ovarian cancer patients have metastatic disease at the time of diagnosis (meaning that the disease has spread beyond the ovaries). Patients who undergo surgery and chemotherapy usually respond to the therapy; however, most patients will eventually relapse and succumb to the disease. Tumor initiating cells (TICs) that express stem cell markers are thought to initiate new tumors contributing to tumor progression and lethality. The central problem we are studying is how TICs are recruited to sites where they will initiate new tumor metastases. We found that a gene called ARID3B is overexpressed in the most common type of ovarian cancer (serous) and that moderate expression of ARID3B in the nucleus correlates with relapse after chemotherapy. Importantly ARID3B promotes tumor growth in an animal model of ovarian cancer. Now we are dissecting how ARID3B promotes tumor growth. We have discovered that ARID3B regulates expression of TIC genes. It potently induces the TIC gene CD133. CD133 is on the surface of cells and has been shown to help in adhesion. We propose that ARID3B regulation of CD133 increases targeting of TICs to the tissues where they establish new tumors. This work is directly relevant to the mission of the Ovarian Cancer Research Program because it will provide critical information on how ovarian TIC/cancer stem cells interact with their environment during the process of metastasis. It will also provide critical evidence on the feasibility of targeting TICs as a treatment option. Finally, through the Teal Scholar program, we will be training a postdoctoral fellow to become a leader in ovarian cancer research. The goals of this study are: (1) Determine if CD133 is necessary for ARID3B induced tumorigenesis. (2) Assess if CD133 increases adhesion to new sites of metastasis. (3) Define mechanism for CD133 recruitment to peritoneal (where ovarian cancer cells frequently metastasize) cells. It is our hope that this body of knowledge will lead to many advances in how ovarian cancer is managed and ultimately treated. We believe that by creating knowledge about what genes/proteins are involved in metastasis, new treatment can be designed that prevents or limits the spread of cancer cells. Our work also suggests that ARID3B may be an important biomarker that can be used to guide physicians in choosing the best treatment plan. ARID3B decreases response to paclitaxel (one of the drugs used to treat ovarian cancer). Therefore, knowing the expression levels of ARID3B would enable oncologists to tailor the treatment plan for many patients. I would predict that this study could lead to a search for drugs that target TIC pathways within the next 10 years. Importantly, this may change how women with ovarian cancer who also have elevated ARID3B in their tumors are treated, prolonging a patient s response to chemotherapy or limiting the toxicity associated with drugs like paclitaxel. These studies have the potential to impact many military families since this year alone 21,980 American women will be diagnosed with ovarian cancer and more than 14,000 will die.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510071
Entities
People
- Karen Cowden Dahl
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army