Project Grant R01CA279689

REWIRING CANCER-INDUCED ABNORMALITIES IN THE VASCULAR BARRIER - SUMMARY TUMORS ARE KNOWN TO INDUCE THE FORMATION OF UNIQUE MICROENVIRONMENTS IN DISTANT ORGANS THAT FACILITATE SEEDING, SURVIVAL, AND GROWTH OF METASTATIC NODULES. THESE SITES, KNOWN AS PRE- METASTATIC NICHES, EMERGE AS A RESPONSE TO THE COMBINED SYSTEMIC EFFECTS OF TUMOR-DERIVED FACTORS AND SHED EXTRACELLULAR VESICLES. ASIDE FROM PREMETASTATIC NICHES, DISTANT ALTERATIONS IN OTHERWISE NORMAL TISSUES OF CANCER-BEARING SUBJECTS HAVE NOT BEEN IDENTIFIED. WHILE EVALUATING THE SYSTEMIC VASCULATURE OF TUMOR-BEARING MICE, WE SERENDIPITOUSLY FOUND THAT PRESENCE OF CERTAIN TYPES OF CARCINOMAS IMPLANTED SUBCUTANEOUSLY HAVE A DELETERIOUS EFFECT ON INTESTINAL LYMPHATICS AND BLOOD VESSELS. THIS SURPRISING FINDING WAS DIRECTLY CORRELATED WITH SEVERE WEIGHT LOSS AND PROGRESSIVE REDUCTION OF SKELETAL MUSCLE MASS, A CONDITION KNOWN AS CACHEXIA. IMPORTANTLY, IN CANCER PATIENTS, CACHEXIA HAS A MEANINGFUL NEGATIVE IMPACT IN THEIR ABILITY TO RESPOND AND RECOVER FROM THERAPY AND THUS IDENTIFICATION OF INDIVIDUALS AT RISK AND EFFECTIVE TREATMENTS TO REVERSE THIS CONDITION ARE IMPERATIVE. BLOCKING CACHEXIA OFFERS NOT ONLY A SIGNIFICANT IMPROVEMENT IN THE QUALITY OF LIFE FOR THESE PATIENTS, BUT IT ALSO IMPROVES TOLERANCE AND RESPONSE TO CANCER TREATMENT, WITH MEASURABLE INCREASE IN SURVIVAL RATES. ALTHOUGH THE CLINICAL CONSEQUENCES OF CACHEXIA AND ITS POSITIVE RESPONSE TO THERAPY ARE WELL KNOWN, READ- OUTS FOR EARLY DIAGNOSIS AND EFFECTIVE TREATMENT REMAIN CHALLENGING. OUR PRELIMINARY FINDINGS UNCOVERED THAT TUMORS WITH HIGH CIRCULATING LEVELS OF SPECIFIC INFLAMMATORY CYTOKINES INDUCED VASCULAR AND LYMPHATIC BARRIER DYSFUNCTION IN THE INTESTINE. IN PARTICULAR, THE CAPILLARIES AND CENTRAL LYMPHATIC LACTEAL OF INTESTINAL VILLI SHOWED PROLONGED AND EXACERBATED LEVELS OF VEGFR2/3 SIGNALING, TAK1 PHOSPHORYLATION AND OTHER ALTERATIONS THAT YIELD COMPROMISED JUNCTIONAL COMPLEXES. IN TURN, WE DOCUMENTED CHANGES IN FOOD ABSORPTION DESPITE UNALTERED LEVELS OF FOOD CONSUMPTION AND ASSOCIATED WEIGHT LOSS. COLLECTIVELY, THE FINDINGS INDICATE THAT CANCER-INDUCED ALTERATIONS IN THE VASCULO-LYMPHATIC COMPARTMENT OF INTESTINAL VILLI CONTRIBUTE TO, AND PERHAPS TRIGGER, THE DEVELOPMENT OF CACHEXIA BY AFFECTING THEIR ABILITY TO ABSORB LIPIDS. THE GOAL OF THIS PROJECT IS TO DETERMINE WHETHER DEFICIENCIES IN LYMPHATIC AND VASCULAR ENDOTHELIUM ARE A SIGNIFICANT UNDERLYING CAUSE OF CANCER-INDUCED CACHEXIA THAT CAN BE TARGETED TO REVERSE THE CONDITION. OUR TWO PROGUED APPROACH WILL DELVE INTO FURTHER UNDERSTANDING OF THE UNDERLYING MOLECULAR MECHANISMS WHILE PURSUING PRE-CLINICAL TRIALS IN MOUSE MODELS TO TEST THERAPEUTIC AVENUES AIMED AT CORRECTING THE VASCULAR DEFICIENCIES. THE CONTRIBUTION OF THE VASCULATURE AS AN IMPORTANT CULPRIT IN CACHEXIA HAS NOT BEEN RECOGNIZED AND IT COULD BE TRANSFORMATIVE AS IT MAY OFFER AN UNPRECEDENTED OPPORTUNITY FOR INTERVENTION AT EARLY STAGES BY FOCUSING ON REWIRING ENDOTHELIAL BARRIER AND BLOCKING THIS DEVASTATING CONDITION.