PROJECT SUMMARY Cachexia is defined as progressive loss of body weight and muscle mass that occurs as a byproduct of chronic diseases, including cancer. It is estimated that musculoskeletal wasting occurs in up to 80% of cancer patients, including colorectal cancer, drastically worsening quality of life and survival. Thus, there is an urgent need to develop new treatments for cancer-induced musculoskeletal wasting. Our recent published observations showing that skeletal wasting occurs even in the absence of direct metastases to the bone, suggest that tumor- derived soluble factors may play a critical role in initiating bone loss. Additionally, our published observations showing that formation of liver metastases in colorectal cancer exacerbates musculoskeletal wasting, suggests a possible role of the liver in mediating skeletal muscle and bone loss. In this regard, my preliminary studies suggest that fibroblast growth factor 21 (FGF21) and liver-insulin-like growth factor binding protein 1 (IGFBP1) contribute to musculoskeletal wasting in colorectal cancer. In preliminary studies, I found that mice bearing subcutaneous MC-38 colorectal tumors present with muscle and bone loss, along with high FGF21 and robust IGFBP1. Interestingly, treatment of hepatocytes with recombinant FGF21 induced IGFBP1 production. Contrarily, mice bearing subcutaneous C26 colorectal tumors, characterized by low FGF21 expression, have muscle loss without bone loss and markedly lower IGFBP1 compared to subcutaneous MC-38 hosts. However, mice bearing C26 liver metastases have exacerbated musculoskeletal wasting and higher IGFBP1 levels compared to mice bearing C26 subcutaneous tumors. Intriguingly, murine myotubes treated with recombinant IGFBP1 undergo atrophy, whereas anti-IGFBP1 neutralizing antibodies preserved myotube size in C2C12 cultures exposed to plasma from mice bearing C26 liver metastases, and C26 hosts infected with AAV- shIGFBP1 maintained muscle mass and strength. Hence, the objective of this proposal is to interrogate the FGF21-IGFBP1 axis in colorectal cancer-associated muscle and bone loss. Based on preliminary data and published work my central hypothesis is that tumor-derived FGF21 promotes cachexia and hepatic production of IGFBP1, which in turn mediates musculoskeletal wasting in colorectal cancer. In Aim 1, I will determine the effects of tumor- and host-derived FGF21 on hepatic IGFBP1 production and musculoskeletal wasting in colorectal cancer without bone metastases. I hypothesize that tumor-derived FGF21 promotes hepatic IGFBP1 and musculoskeletal wasting. In Aim 2 I will determine the IGFBP1-depedent effects on musculoskeletal wasting in colorectal cancer. I hypothesize that IGFBP1 promotes musculoskeletal wasting in colorectal cancer. The findings from the proposed studies will identify the FGF21-IGFBP1 axis as a novel therapeutic target for the treatment of muscle and bone wasting in colorectal cancer and will open new avenues for cachexia resea...