Project Grant F31CA318736

TAZ-TEAD SIGNALING IN THE IMMUNE MICROENVIRONMENT OF CUTANEOUS MELANOMA - ABSTRACT CURRENT STANDARD OF CARE TREATMENT FOR LATE-STAGE CUTANEOUS MELANOMA IS IMMUNE CHECKPOINT BLOCKADE (ICB); HOWEVER, ~50% OF PATIENTS DO NOT RESPOND. MECHANISMS UNDERLYING INNATE ICB RESISTANCE AND CROSS RESISTANCE TO ICB AND MAPK TARGETED THERAPY (TT) ARE ACTIVELY BEING INVESTIGATED. OF NOTE, AN INVASIVE, MESENCHYMAL-LIKE CELL STATE, OFTEN CHARACTERIZED BY LOW EXPRESSION OF SOX10 AND ENHANCED YAP/TAZ-TEAD SIGNALING, IS ASSOCIATED WITH CROSS RESISTANCE TO ICB AND TT. OUR LAB HAS PREVIOUSLY SHOWN TT RESISTANT MELANOMA CELLS EXHIBIT A STRONG DEPENDENCE ON TAZ-TEAD SIGNALING FOR SURVIVAL. YAP AND TAZ ARE PARALOGS, ACTING AS TRANSCRIPTIONAL CO-ACTIVATORS TO TEAD TRANSCRIPTION FACTORS TO PROMOTE EXPRESSION OF GENES INCLUDING PD-L1. HOWEVER, YAP AND TAZ HAVE CONTEXT-DEPENDENT FUNCTIONS WITHIN THE TUMOR IMMUNE MICROENVIRONMENT. WE SHOW THAT TAZ-DEPENDENT GENES ARE ENRICHED IN ICB NON-RESPONDERS. THEREFORE, OUR STUDIES AIM TO INVESTIGATE THE ROLE OF TAZ-TEAD SIGNALING IN THE IMMUNE MICROENVIRONMENT AND EVALUATE ITS RELEVANCE IN THE CONTEXT OF ICB. IN MELANOMA CELLS WITH HIGH TEAD ACTIVITY, WE DEMONSTRATE TAZ-DEPENDENT EXPRESSION OF IMMUNE-MODULATORY MOLECULES SUCH AS PD-L1, GALECTIN 3, GALECTIN 9 AND OX40 LIGAND (OX40L). IN VIVO ANALYSIS OF TUMORS TREATED SHORT-TERM WITH TEAD INHIBITOR (VT103) REVEALED PRO-INFLAMMATORY CHANGES IN THE IMMUNE MICROENVIRONMENT, INCLUDING UPREGULATION OF MHC-I, OX40L AND GALECTIN 9 ON TUMOR CELLS AND ENHANCED INFILTRATION OF CD4+ T CELLS. TOGETHER, THESE DATA IMPLY THERE IS TAZ-TEAD DEPENDENT REGULATION OF IMMUNE-MODULATORY MOLECULES IN THE MICROENVIRONMENT, SUGGESTING THAT TARGETING TEADS MAY ENHANCE SENSITIVITY OF TUMORS TO ICB. WE WILL INVESTIGATE THE MECHANISTIC ROLE OF TAZ-TEAD IN THE IMMUNE MICROENVIRONMENT UTILIZING BOTH SECRETOME ANALYSIS AND AN IN VIVO INDUCIBLE OVEREXPRESSION SYSTEM. ADDITIONALLY, WE WILL EVALUATE THE ABILITY OF CLINICALLY RELEVANT TEAD INHIBITORS TO ENHANCE MELANOMA RESPONSE TO ICB THERAPY. THESE STUDIES WILL PROVIDE NEW INSIGHT INTO UNDERLYING MECHANISMS OF ICB RESISTANCE IN CUTANEOUS MELANOMA. THROUGH THIS PROPOSAL, I WILL DEVELOP MY PROFICIENCY IN THE IMMUNE-ONCOLOGY FIELD WHILE IMPROVING MY SCIENTIFIC COMMUNICATION AND CRITICAL THINKING SKILLS. COMPLETION OF MY FELLOWSHIP TRAINING AT THOMAS JEFFERSON UNIVERSITY WILL ENSURE I AM EQUIPPED WITH THE TOOLS TO ACHIEVE MY LONG-TERM GOAL OF BECOMING AN ACADEMIC CANCER BIOLOGIST.