Project Grant F31CA309886

ALTERED ADIPOSE TISSUE METABOLISM FOLLOWING RADIATION DRIVES PROSTATE CANCER METASTASIS - PROJECT SUMMARY NEARLY A THIRD OF PROSTATE CANCER (PCA) PATIENTS RECEIVE RADIATION THERAPY AS PART OF THEIR TREATMENT REGIMEN. THOSE PATIENTS TREATED WITH RADIOTHERAPY ARE AT A HIGHER RISK OF DISEASE RECURRENCE 5+ YEARS AFTER TREATMENT, BUT IT IS NOT KNOWN WHY. DURING RADIATION TREATMENT, THE ADIPOSE TISSUE FOUND IN THE PELVIC REGION IS NOT COMMONLY SPARED AND, THEREFORE, EXPOSED TO THE HARMFUL EFFECTS OF RADIATION. CURRENTLY, THE IMPACT THAT RADIATION HAS ON ADIPOCYTE FUNCTION HAS BEEN MINIMALLY INVESTIGATED. I HAVE RECENTLY PUBLISHED THAT UPON EXPOSURE OF ADIPOSE TISSUE TO CLINICALLY RELEVANT HYPOFRACTIONATED DOSING OF RADIATION, ADIPOSE TISSUE BECOMES OXIDATIVELY DAMAGED, INFLAMED, AND EXHIBITS INCREASED LIPOLYTIC ACTIVITY COMPARED TO UNIRRADIATED ADIPOSE TISSUE. THE DAMAGE THAT RADIATION CAN CAUSE TO ADIPOSE TISSUE CONTINUES TO PERSIST CHRONICALLY. INTERESTINGLY, I HAVE DEMONSTRATED THAT IRRADIATED ADIPOCYTES PROMOTE PCA METASTASIS, BOTH IN VITRO AND IN VIVO. LIPID TRACING EXPERIMENTS AND PHARMACOLOGICAL LIPASE INHIBITORS REVEALED THAT ADIPOCYTE-SUPPLIED LIPIDS, RELEASED UPON IRRADIATION, INDUCE PCA MIGRATION. BASED ON THESE EXCITING FINDINGS, I HYPOTHESIZE THAT IRRADIATED ADIPOCYTES PRODUCE EXCESS ROS, WHICH ENHANCES LIPOLYSIS AND RELEASES FATTY ACIDS, WHICH ARE INTERNALIZED BY PCA CELLS TO PROMOTE METASTASIS THROUGH INCREASED CPT1A EXPRESSION AND B-OXIDATION. I PROPOSE TO USE A MULTI-FACETED APPROACH, INCLUDING SEAHORSE XF, ELECTRON MICROSCOPY, LIPIDOMIC-BASED APPROACHES, GENE MANIPULATION, AND IN VIVO MODELING TO EXPLORE A NOVEL RELATIONSHIP BETWEEN IRRADIATED ADIPOSE TISSUE AND PCA METASTASIS. EXPERIMENTS PROPOSED IN AIM 1 WILL ELUCIDATE HOW RADIATION-INDUCED ROS IS LINKED TO THE UPREGULATION OF LIPOLYSIS THROUGH PROTEIN KINASE A (PKA) BY UTILIZING ROS SCAVENGERS BMX-001 AND VITAMIN E. AIM 1 ALSO AIMS TO IDENTIFY DIFFERENTIALLY SECRETED LIPID SPECIES FROM THE IRRADIATED VERSUS UNIRRADIATED ADIPOCYTES BY COLLABORATING WITH VARIOUS PEOPLE ACROSS THE UNIVERSITY OF NEBRASKA SYSTEM TO RUN AND ANALYZE LIPIDOMIC SAMPLES. AIM 2 WILL INVESTIGATE WHETHER LIPID UPTAKE FROM IRRADIATED ADIPOCYTES INCREASES CPT1A LEVELS AND B-OXIDATION TO INDUCE PCA MIGRATION. FIRST, I WILL DETERMINE WHAT LIPIDS ARE BEING TAKEN UP BY PCA CELLS WHEN IN CROSSTALK WITH IRRADIATED ADIPOSE TISSUE BY UTILIZING 13C-ISOTOPIC LABELED LIPIDS. THEN, THE ROLE OF FATTY ACID OXIDATION IN PCA MIGRATION WILL BE ASSESSED BY LOOKING AT MITOCHONDRIA-LIPID DROPLET CONTACT SITES AND MANIPULATING THE CPT1A GENE. LASTLY, THE ROLE OF CANCER CELL FATTY ACID OXIDATION IN INDUCING METASTASIS WILL BE EVALUATED USING AN ORTHOTOPIC PCA MOUSE MODEL. THE RESULTS OF THIS PROPOSAL WILL ESTABLISH A FUNDAMENTAL MECHANISM BY WHICH IRRADIATED ADIPOSE TISSUES INDUCE PCA METASTASIS, WHICH MAY EXPLAIN WHY PATIENTS RECEIVING RADIATION ARE AT A GREATER RISK OF RECURRENCE. THE PROPOSED WORK WILL GREATLY ENHANCE MY RESEARCH TRAINING AND PROPEL ME TO THE NEXT STAGE IN MY CAREER THROUGH EXPOSURE TO NEW TECHNIQUES AND THE OPPORTUNITY TO PRESENT AND COMMUNICATE THIS WORK TO THE SCIENTIFIC COMMUNITY.