The Function of NFAT3 in Ovarian Cancer Cell Quiescence and Chemotherapy Resistance
Abstract
The majority of deaths from ovarian cancer are related to disease recurrence and the development of chemotherapy-resistant disease. With the exception of better screening tests, preventing chemotherapy resistance is arguably the most likely means to directly improve the cure rate for patients with ovarian cancer. While most patients show complete clinical response to surgical removal of tumors and traditional chemotherapy, in many cases a few ovarian cancer cells will survive chemotherapy treatments and form new tumors. Once tumors recur, they will inevitably become chemotherapy-resistant and result in patient death. This proposal addresses a unique and difficult-to-study mechanism that could cause primary cancer cells to be resistant to chemotherapy: quiescence. Quiescence is an attribute of stem cells. Quiescent cells are alive but, unless stimulated, either do not divide or divide very slowly. Based on the fact that they are slowly dividing, quiescent cells are suspected of being inherently resistant to chemotherapy, which targets rapidly dividing cells. Unfortunately, quiescence as a mechanism of chemoresistance has been understudied due to the technical difficulty of identifying/studying rare, quiescent cells in a sea of rapidly dividing cancer cells. A perfect example of chemotherapy resistance and quiescent stem cells is the human hair follicle. The majority of cells in the hair follicle are rapidly growing. Chemotherapy targets these rapidly dividing hair cells and causes hair loss. However, the stem cells within the hair follicle are quiescent. These cells are resistant to chemotherapy, and therefore once chemotherapy ends, all patients re-grow their hair. Quiescence of the hair follicle stem cell is regulated by NFAT1, a "master" regulator of cellular gene expression. Interestingly, we have found that ovarian cancer stem cells also express an NFAT homolog, NFAT3. Furthermore, our preliminary data indicate that increased expression of NFAT3 slows ovarian cancer cell growth. We hypothesize that, parallel to NFAT1 s function in hair-follicle stem cells, NFAT3 will regulate ovarian cancer cell quiescence, leading to chemoresistance and tumor recurrence. As an extension of this hypothesis, we predict that compounds that inhibit NFAT3 could reduce/prevent cancer cell chemotherapy resistance and potentially reduce relapse rates. Furthermore, compounds that activate NFAT3 could be used after completion of chemotherapy to induce stem cell quiescence and thus delay disease recurrences. We propose to directly test the role of NFAT3 in inducing ovarian cancer cell quiescence. More importantly, we will directly test the impact of pharmacologic NFAT activation and inhibition on chemotherapy resistance and progression-free survival in vivo. Finally, we will determine if NFAT3 predicts patient outcomes. We believe our studies could be groundbreaking in the field. As both inhibitors and activators of the NFAT signaling axis already exist, these drugs could be repurposed for direct translation into clinical trials.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510083
Entities
People
- Ronald Buckanovich
Organizations
- United States Army
- University of Michigan