Project Grant F30CA294670

THE EFFECTS OF OVULATION ON FALLOPIAN TUBE-DERIVED TUMORIGENESIS USING MICROFLUIDIC PREDICT-MOS PLATFORM - PROJECT SUMMARY/ABSTRACT HIGH GRADE SEROUS OVARIAN CANCER (HGSOC) IS THE MOST PREVALENT AND LETHAL HISTOTYPE OF OVARIAN CANCER. THE FALLOPIAN TUBE IS THE PRIMARY ORIGIN OF MOST HGSOCS, SUPPORTED BY EVIDENCE FROM MOLECULAR ANALYSIS AND CLINICALLY DEMONSTRATED BY THE PROTECTIVE EFFECT OF SALPINGECTOMY. OVULATION IS A MAJOR RISK FACTOR FOR OVARIAN CANCER. CURRENTLY, THE ONLY MEANS FOR PREVENTION ARE THROUGH THE REDUCTION OF LIFETIME OVULATORY EVENTS, SUCH AS THROUGH THE USE HORMONAL BIRTH CONTROL OR SURGICAL REMOVAL OF THE FALLOPIAN TUBES AND OVARIES. THE COMPLEXITY IN UNDERSTANDING THE DYNAMIC INTERPLAY BETWEEN OVARIAN SECRETIONS AND FALLOPIAN TUBE EPITHELIUM (FTE) IS COMPOUNDED BY THE DEEP-SEATED ABDOMINAL LOCATION AND THE ELUSIVE DISPERSION OF FLUIDS SECRETED BY THE OVARY INTO THE PERITONEAL SPACE. THEREFORE, THE MOLECULAR MECHANISMS THAT DRIVE THE INITIATION OF OVARIAN CANCER IN THE FALLOPIAN TUBE IN RESPONSE TO OVULATION ARE POORLY UNDERSTOOD. TO ADDRESS THESE CHALLENGES, OUR COLLABORATIVE TEAM HAS DEVELOPED A PHYSIOLOGICALLY ACCURATE MENSTRUAL CYCLE MODEL USING THE PREDICT MULTI-ORGAN SYSTEM (MOS), A MICROFLUIDIC (ORGAN-ON-CHIP) DEVICE THAT ENABLES US TO RECAPITULATE THE PROCESS OF OVULATION AND CAPTURE THE ENTIRETY OF OVARIAN SECRETIONS. ADDITIONALLY, OUR LAB ENGINEERED PRENEOPLASTIC MURINE OVIDUCTAL EPITHELIAL (MOE) CELL MODELS (EQUIVALENT TO THE HUMAN FALLOPIAN TUBE) THAT EXPRESS THE MOST COMMONLY AND EARLIEST IDENTIFIED ABERRATIONS IN HGSOC: PAX2 LOSS AND P53 MUTATION (R2723H). UTILIZING OVULATION SECRETIONS CAPTURED ON THE PLATFORM, WE OBSERVED AN UPREGULATION OF DNA DAMAGE RESPONSE TRANSCRIPTS IN THE FALLOPIAN TUBE MODELS, FOLLOWED BY AN INCREASE IN PROLIFERATION CAUSED BY SECRETIONS FROM THE LUTEAL PHASE IN OUR PAX2 DEFICIENT CELLS. THESE FINDINGS ARE SIGNIFICANT, AS THEY DEMONSTRATE THAT OVARIAN SECRETIONS INDUCE DNA DAMAGE AND PROLIFERATION IN THE FTE. OUR PROPOSED AIMS ENCOMPASS UNDERSTANDING THE PATHWAYS ASSOCIATED WITH DNA DAMAGE, OXIDATIVE STRESS, AND CELL MIGRATION CAUSED BY OVULATION AS WELL AS UNCOVERING THE MOLECULAR PATHWAYS THAT DRIVE FTE PROLIFERATION IN THE LUTEAL PHASE. ADDITIONALLY, WE WILL INVESTIGATE THE IN VITRO EFFICACY OF A COX2 INHIBITOR TO ACT AS A POTENTIAL CHEMOPREVENTATIVE AGENT AND TO MITIGATE THE DAMAGING EFFECTS OF OVULATION. WITH INCREASING INTEREST IN NON-HORMONAL BIRTH CONTROL METHODS, OUR PROPOSAL REPRESENTS A STEP TOWARDS INVESTIGATING A NON-HORMONAL STRATEGY FOR PREVENTION. THROUGH THE EXPERIMENTS OUTLINED IN THIS PROPOSAL, WE AIM TO IDENTIFY THE EARLY MECHANISMS INVOLVED IN HGSOC INITIATION BY STUDYING PHASE-DEPENDENT CHANGES CAUSED BY SECRETIONS FROM THE OVARY. THE RESEARCH PROJECT AND STRATEGIES WILL FACILITATE MY TRAINING AS A PHARMD/PHD STUDENT GIVEN THEIR FOCUS ON UNCOVERING MECHANISMS AND TREATMENTS FOR HGSOC.