Project Grant F31CA310639

INVESTIGATING THE EFFECT OF HIGH METHIONINE AVAILABILITY ON CANCER PROGRESSION - ABSTRACT MOST POTENTIAL CANCER THERAPEUTICS DO NOT TRANSLATE FROM THE LAB TO THE CLINIC, AND ONE MAJOR REASON IS THE LIMITED USE OF APPROPRIATE PRECLINICAL MODELS. IN VITRO STUDIES TYPICALLY RELY ON STANDARD CULTURE MEDIA THAT CONTAIN OVERSATURATED NUTRIENT LEVELS, WHILE IN VIVO STUDIES RARELY INCORPORATE AGED ANIMALS, DESPITE THE FACT THAT MOST CANCERS ARE DIAGNOSED IN OLDER ADULTS. THESE ARTIFICIAL CONDITIONS CAN MASK OR DISTORT THE TRUE METABOLIC DEPENDENCIES OF TUMORS AND MAY CONTRIBUTE TO THE POOR TRANSLATION OF METABOLIC THERAPIES. THIS PROPOSAL ADDRESSES THESE GAPS BY USING PHYSIOLOGICAL MEDIA IN VITRO AND AGED MOUSE MODELS IN VIVO TO IDENTIFY METABOLIC DRIVERS OF CANCER CELL PROLIFERATION THAT ARE MORE LIKELY TO TRANSLATE SUCCESSFULLY INTO PATIENTS. ALTERED METABOLISM IS A HALLMARK OF CANCER, AS ILLUSTRATED BY APPROVED METABOLIC THERAPIES SUCH AS THE FOLATE CYCLE INHIBITOR METHOTREXATE. YET MANY METABOLIC THERAPIES HAVE FAILED CLINICALLY DESPITE PROMISING PRECLINICAL RESULTS, IN PART DUE TO THE USE OF MEDIA LIKE DMEM AND RPMI, WHICH WERE FORMULATED TO MAXIMIZE PROLIFERATION RATHER THAN MIMIC HUMAN PLASMA. SUCH DISCREPANCIES CAN CREATE SYNTHETIC METABOLIC SENSITIVITIES. FOR EXAMPLE, SERINE AND GLYCINE DEPRIVATION DECREASES PROLIFERATION IN SEVERAL CANCER LINES IN DMEM BUT NOT IN PHYSIOLOGICAL MEDIA. PHYSIOLOGICAL MEDIA, SUCH AS HUMAN PLASMA-LIKE MEDIA (HPLM), WERE DEVELOPED TO REPLICATE THE METABOLIC COMPOSITION OF HUMAN PLASMA. OUR PRELIMINARY STUDIES SHOW THAT BLADDER, LIVER, AND LUNG CANCER CELL LINES PROLIFERATE SIGNIFICANTLY SLOWER IN HPLM THAN IN DMEM. IN HCC LINES, METHIONINE WAS THE ONLY AMINO ACID CAPABLE OF RESCUING PROLIFERATION, A FINDING THAT IS CONSERVED ACROSS BLADDER AND LUNG CANCER LINES. SUPPLEMENTING HPLM WITH OTHER METHIONINE-CYCLE METABOLITES, SUCH AS HOMOCYSTEINE, ALSO PARTIALLY RESCUES PROLIFERATION, UNDERSCORING CANCER CELLS' RELIANCE ON THE METHIONINE CYCLE. IMPORTANTLY, METHIONINE METABOLISM BECOMES DYSREGULATED IN THE AGING MOUSE BLADDER, AND AGED SERUM INCREASES BLADDER CANCER CELL PROLIFERATION AND MIGRATION. GIVEN THAT BLADDER CANCER HAS THE OLDEST AVERAGE AGE OF DIAGNOSIS OF ANY CANCER, AGE-ASSOCIATED METABOLIC CHANGES MAY STRONGLY INFLUENCE TUMOR BEHAVIOR. TOGETHER, THESE FINDINGS SUGGEST THAT STUDYING HIGH METHIONINE AVAILABILITY USING BOTH PHYSIOLOGICAL MEDIA AND AGED MODELS IS A POWERFUL STRATEGY TO UNCOVER METABOLIC VULNERABILITIES THAT MAY BE ESPECIALLY PRONOUNCED IN OLDER TUMORS. IN THIS PROPOSAL, WE WILL INVESTIGATE THE MECHANISMS THAT DRIVE CANCER CELL PROLIFERATION UNDER HIGH METHIONINE CONDITIONS, DETERMINE HOW HIGH METHIONINE DIETS AFFECT BLADDER TUMOR GROWTH AND IMMUNE COMPOSITION IN VIVO, AND ASSESS WHETHER THESE EFFECTS DIFFER BETWEEN YOUNG AND OLD MICE. I ALSO OUTLINE THE PROFESSIONAL GOALS I AIM TO ACCOMPLISH DURING THIS FELLOWSHIP, INCLUDING: 1) ACQUIRING ADVANCED LABORATORY SKILLS, 2) TAKING ON LEADERSHIP ROLES WITHIN AND OUTSIDE THE LAB, AND 3) STRENGTHENING MY SCIENTIFIC COMMUNICATION ABILITIES. WITH THE SUPPORT OF MY MENTOR AND THE RESOURCES AVAILABLE AT USC, I AM CONFIDENT THAT I CAN ACHIEVE THESE GOALS AND GROW INTO A STRONG, INDEPENDENT CANCER RESEARCHER.