Project Grant F31CA290773

MANIPULATION OF THE GUT MICROBIOME TO DELAY BREAST CANCER ONSET AND PROGRESSION IN THE CONTEXT OF WEIGHT LOSS AND OBESITY - SUMMARY BARIATRIC SURGERY IS ASSOCIATED WITH REDUCED BREAST CANCER (BC) RISK, IMPROVED OUTCOMES, AND INCREASED IMMUNOTHERAPY EFFICACY, BUT MECHANISMS REMAIN UNDEFINED. BY EXAMINING THE UNDERLYING MECHANISMS OF BARIATRIC SURGERY-INDUCED PROTECTION, NOVEL THERAPEUTIC APPROACHES MAY BE IDENTIFIED TO BENEFIT BOTH LEAN AND OBESE PATIENTS. LONG-TERM CHANGES IN GUT MICROBIOME COMPOSITION AND ABUNDANCE PERSIST AT LEAST 5 YEARS POST BARIATRIC SURGERY, WHICH I POSIT WILL RESULT IN MODULATION OF CIRCULATING MICROBIALLY DERIVED METABOLITES. MICROBIALLY DERIVED METABOLITES, INCLUDING SHORT CHAIN FATTY ACIDS, SECONDARY BILE ACIDS, AND AMINO ACIDS, ARE PRODUCED OR MODIFIED BY GUT MICROBES. THESE METABOLITES CAN ACT LOCALLY IN THE GUT AND CIRCULATE SYSTEMICALLY AS ENDOCRINE SIGNALING MEDIATORS TO MODULATE HOST ENERGY METABOLISM, IMMUNE HOMEOSTASIS, AND, PRESUMABLY, ANTI-TUMOR IMMUNITY. PRELIMINARY DATA SUGGESTS THAT DEPLETION OF SECONDARY BILE ACIDS IN COMBINATION WITH ELEVATION OF BRANCHED CHAIN AMINO ACIDS INCREASED TUMOR IMMUNE INFILTRATION AND MEDIATED INCREASED RESPONSE TO APD-L1 IMMUNOTHERAPY. ADDITIONAL EXCITING PRELIMINARY DATA DEMONSTRATES THAT TRANSFER OF GUT MICROBIOTA FROM BARIATRIC SURGICAL WEIGHT LOSS MOUSE AND HUMAN DONORS TO NON-SURGICAL RECIPIENT MICE DECREASED TUMOR BURDEN. HOWEVER, THE PRECISE INTERACTIONS BETWEEN THE GUT MICROBIOME, MICROBIALLY DERIVED METABOLITES, AND IMMUNE FUNCTION IN BC REMAINS UNCLEAR AND WILL BE INVESTIGATED IN THIS F31 PROPOSAL. I HYPOTHESIZE THAT MODULATION OF THE GUT MICROBIOTA WILL IDENTIFY SPECIFIC METABOLITES ACTIVATING ANTI-TUMOR IMMUNITY THAT MIMIC THE EFFECTS OF BARIATRIC SURGERY. AIM 1 WILL DETERMINE THE CONTRIBUTION OF GUT MICROBIOTA TO IMPROVED OUTCOMES OF BC AFTER BARIATRIC SURGERY. FECAL MICROBIAL TRANSPLANT (FMT) WILL INVESTIGATE TO WHAT EXTENT MICROBIOTA CAN TRANSFER BARIATRIC SURGERY- ASSOCIATED ANTI-TUMOR EFFICACY FROM DONOR MICE TO REDUCE CANCER BURDEN IN RECIPIENTS. COMPLEMENTARY MODELS IN ER+ AND ER- BC WILL ALLOW ME TO COMPARE IMPACTS ON DIFFERENT BC SUBTYPES. EXISTING PATIENT FECAL SAMPLES PRE- AND POST-BARIATRIC SURGERY WILL NEXT BE EXAMINED BY FMT TO IDENTIFY CONSERVED MICROBIOME CHANGES WITH STRONG MECHANISTIC POTENTIAL IN BC. AIM 2 WILL DETERMINE THE IMPACT OF SECONDARY BILE ACIDS ON BC PROGRESSION USING COMPLEMENTARY IN VIVO MODELS AND INNOVATIVE IN VITRO APPROACHES. TAKEN TOGETHER, THIS PROPOSAL WILL DEFINE THE EFFECTS OF MICROBIALLY DERIVED METABOLITES ON THE TUMOR MICROENVIRONMENT, ESPECIALLY REGARDING OBESITY AND IMMUNITY. THIS STUDY BUILDS UPON MY PREVIOUS EXPERIENCE IN MICROBIOLOGY AND IN VITRO ORGANOID MODELING TO SHAPE A HIGHLY COMPETITIVE SKILL SET FOCUSING ON MICROBIOME - IMMUNE SYSTEM INTERACTIONS THROUGH DIVERSE YET COMPLEMENTARY TRAINING INCORPORATING BIOINFORMATICS ANALYSIS AND WET LAB TECHNIQUES IN THE FIELDS OF MICROBIAL GENETICS AND IMMUNOLOGY. THIS F31 WILL TRAIN ME AS AN EXPERT IN THE GUT MICROBIOME, A RAPIDLY EVOLVING AREA OF RESEARCH WITH STRONG THERAPEUTIC POTENTIAL TO HELP TREAT PATIENTS WITH BC AND OTHER DISEASES. THE PROPOSED CROSS- DISCIPLINARY TRAINING DEFINED IN THIS F31 WILL PREPARE ME FOR MY LONG-TERM GOAL OF BECOMING AN INDEPENDENT INVESTIGATOR AT AN ACADEMIC INSTITUTION.