37 | Characterization of novel cancer cachexia preclinical models implementing chemotherapy and surgery

Emma Elisabeth Cappellato, C. Fornelli, N.E. Cortez, V. Schiavo, P. Costelli, F. Penna | Department of Clinical and Biological Sciences, University of Torino, Italy.

Cancer cachexia (CC) is a multifactorial syndrome characterized by weight loss, metabolic alterations, and muscle wasting. Although the C26-mouse model is widely used to study CC, its rapid tumor growth and lack of metastasis fail to recapitulate cancer patient’s trajectory. In colorectal cancer, standard treatment includes chemotherapy and resection of the primary tumor, often followed by tumor relapse and/or metastasis. This study aims to characterize novel C26-based experimental protocols to investigate tissue-specific metabolic changes. Three treatment protocols were evaluated in 3-month-old female BALB/c mice subcutaneously inoculated with 5×10⁵ colon carcinoma cells (C26). Each protocol combined FOLFOX chemotherapy with surgical resection: (1) two doses pre-resection (C26+2F), (2) two doses pre- and post-resection (C26+4F), and (3) a single dose pre-resection (C26+F). Tumors were surgically excised 4 days post-chemotherapy. A group of control mice was included in each experiment. At sacrifice, muscles and tissues were collected for biochemical, histological, and metabolomic analyses. Tumor-bearing mice showed signs of cachexia in all experiments, with increasing severity according to chemotherapy duration. Few mice showed no evidence of primary tumor relapse, fully recovering their body weight and muscle mass. Others progressed to lung metastases, indicating that curative interventions lead to distinct trajectories even in syngeneic mice. Metabolomics analysis in gastrocnemius and liver revealed distinct metabolic profiles of control and tumor-bearing mice, with the no relapsing mice clustering closer to the controls. Muscle and liver exhibit distinct metabolic alterations, showing signs of potential recovery depending on treatment strategy and early intervention. Further investigations are required to identify affected metabolic pathways associated with either bad prognosis or cancer survivorship and recovery.