PROJECT SUMMARY Colorectal cancer (CRC) is frequently accompanied by the development of cachexia, a multi-systemic wasting syndrome that affects the majority of patients, especially when the disease recurs by forming liver metastases (LMs). Muscle and bone loss are amongst the most detrimental symptoms of cachexia and directly cause increased morbidity and mortality. We and others have shown that CRC also promotes metabolic and genomic perturbations of the liver, and further, that formation of LMs exacerbates muscle and bone wasting. Unfortunately, no cure is available for cachexia, and research on liver contribution to musculoskeletal wasting in cancer has been lacking; hence, there is an urgent need to develop novel treatments for cachexia-related musculoskeletal symptoms. In this regard, our preliminary findings suggest that IGFBP1, a liver-derived hormone belonging to the insulin-like growth factor family of binding proteins (IGFBPs), plays a causative role in cancer- associated musculoskeletal complications. In our preliminary studies, IGFBP1 was found elevated in CRC patients and in CRC hosts, along with muscle and bone loss. IGFBP1 induced myotube atrophy and osteoclast differentiation. Mice bearing subcutaneous C26 CRC displayed muscle atrophy, but no bone loss, whereas mice bearing C26 LMs showed marked muscle and bone wasting, along with dramatically elevated IGFBP1. Anti-IGFBP1 treatments prevented CRC-induced myofiber atrophy and osteoclastogenesis in vitro, whereas depletion of liver IGFBP1 abolished bone loss and improved muscle wasting in CRC hosts. IGFBP1 was also found elevated in mixed hepatocyte-CRC cultures and in the liver of metastatic CRC hosts, suggesting a role of IGFBP1 in cancer dissemination. The objective of this proposal is to define the mechanisms by which IGFBP1 drives bone loss and contributes to muscle wasting in CRC. Our central hypothesis is that elevated IGFBP1 exacerbates CRC-induced cachexia by triggering events consistent with musculoskeletal wasting. In Aim 1, we will determine the mechanism(s) by which IGFBP1 triggers bone loss in CRC. We hypothesize that in CRC elevated IGFBP1 signals through ITGB1 and promotes osteoclastogenesis, hence bone loss. In Aim 2, we will elucidate the mechanism(s) by which IGFBP1 causes muscle wasting in CRC. We hypothesize that high IGFBP1 participates in muscle atrophy. In Aim 3, we will explore the role of the liver microenvironment in the exacerbation of CRC cachexia. We hypothesize that tumor dissemination to the liver determines changes in gene expression in both hepatocytes and cancer cells consistent with enhanced growth rates and altered expression of IGFBP1 and other liver- and tumor-derived soluble factors. Our findings will define the mechanistic effects of IGFBP1 in cachexia and identify IGFBP1 as a new therapeutic target for the treatment of multi-organ complications in CRC. These results will also open new avenues for cachexia research.