ELUCIDATING TUMOR CELL CTGF-TGF-B SIGNALING AXIS IN DRIVING PANCREATIC CANCER CACHEXIA - PROJECT SUMMARY APPROXIMATELY 50% OF ALL INDIVIDUALS DIAGNOSED WITH CANCER WILL PRESENT WITH CACHEXIA, A DISEASE CAUSED BY SYSTEMIC INFLAMMATION AND DYSMETABOLISM THAT IS CHARACTERIZED AS INVOLUNTARY WEIGHT LOSS LARGELY ATTRIBUTED TO LOSS OF SKELETAL MUSCLE MASS. INDIVIDUALS WITH CANCER CACHEXIA ARE LESS TOLERANT TO CANCER TREATMENTS, RESULTING IN DETERIORATION OF PHYSICAL FUNCTION, AND REDUCED SURVIVAL. DESPITE CACHEXIA BEING A MAJOR PREDICTOR OF POOR OUTCOMES IN THESE INDIVIDUALS, THERE ARE NO CURRENT APPROVED EFFECTIVE THERAPIES TO PRESERVE OR REVERSE MUSCLE MASS LOSS IN THIS PATIENT POPULATION. THIS CALLS FOR FURTHER MECHANISTIC STUDIES RESPONSIBLE FOR DRIVING CANCER-ASSOCIATED CACHEXIA. CONNECTIVE TISSUE GROWTH FACTOR, ALSO KNOWN AS CELLULAR COMMUNICATION NETWORK FACTOR 2 (CTGF/CCN2) HAS BEEN IDENTIFIED THROUGH THE SPONSOR R01 (R01CA270025) AS A KEY DRIVER OF SKELETAL MUSCLE WASTING. UNPUBLISHED DATA COLLECTED FROM THIS AWARD DEMONSTRATES THAT SYSTEMIC NEUTRALIZATION OR GENETIC KNOCKOUT OF CTGF FROM MURINE PANCREATIC CANCER (KPC) CELLS IS PROTECTIVE AGAINST CACHEXIA PATHOLOGIES, INCLUDING SKELETAL MUSCLE WASTING, RESPIRATORY MUSCLE REMODELING, AND SYSTEMIC INFLAMMATION. THIS PROPOSAL WILL SPECIFICALLY INVESTIGATE THE ROLE OF TUMOR CELL-DERIVED CTGF IN PROMOTING SKELETAL MUSCLE PATHOLOGY ASSOCIATED WITH CACHEXIA THROUGH A TGF-B-DEPENDENT SIGNALING AXIS. PRELIMINARY STUDIES FROM OUR LAB HAVE DEMONSTRATED THAT IMPLANTATION OF KPC CELLS LACKING CTGF PREVENTS THE UPREGULATION OF BOTH TGF-B2 AND TGF-B3 WITHIN THE CIRCULATION, WITH THE REPRESSION OF TGF-B3 MOST STRONGLY ASSOCIATED WITH THE SPARING OF MUSCLE MASS. RNA-SEQ AND ANALYSIS OF FACTORS SECRETED FROM KPC CELLS SUPPORT CTGF AS KEY UPSTREAM MEDIATOR OF BOTH TGFB TRANSCRIPTION AND TGF-B ACTIVITY. BASED ON THESE DATA, AIM 1 WILL UTILIZE BOTH IN VITRO AND IN VIVO METHODS TO INVESTIGATE THE AUTOCRINE AND PARACRINE ROLES OF CTGF IN MODULATING TGF-B PRODUCTION WITHIN KPC TUMORS, AND ITS ROLE IN MODULATING THE IMMUNE LANDSCAPE OF THE TUMOR MICROENVIRONMENT, WHICH IS KNOWN TO BE INFLUENCED BY TGF-B. AIM 2 WILL INVESTIGATE TGF-B3 AND DIRECT SIGNALING THROUGH THE TGF-B RECEPTOR EXPRESSED IN SKELETAL MUSCLE TISSUE AS A MECHANISM CONTRIBUTING TO KPC-INDUCED MUSCLE LOSS THAT IS REGULATED BY CTGF.