Examining The Skeletal Muscle Microenvironment And Extracellular Matrix With Cancer Cachexia

Cachexia is characterized by the loss of skeletal muscle mass and function leading to reduced quality of life, poor treatment outcomes, and worsened survival in cancer patients. While skeletal muscle fibrosis is a key pathological feature associated with disproportionate muscle weakness, the role of infiltrating immune cells and fibro-adipogenic progenitors (FAPs) in cancer-induced muscle fibrosis is not well understood. PURPOSE: Therefore, the purpose of this study is to examine the role of skeletal muscle immune cells and FAPs in cancer-induced muscle fibrosis and excessive extracellular matrix (ECM) collagen deposition using the colon-26 adenocarcinoma (C26) preclinical model of cancer cachexia. METHODS: CD2F1 male mice (n = 30) were implanted with [106] C26 (cachectic), CT-26 (weight stable), or underwent sham surgery (control). Cachexia indices were assessed and skeletal muscle immune cell populations, satellite cells, and FAPs were examined using high-dimensional flow cytometry. Skeletal muscle morphology and ECM ultrastructure were assessed via decellularized muscle samples and imaged using scanning electron microscopy. RESULTS: Compared to weight stable and non-tumor bearing controls, cachectic mice had significant decreases in body weight (-13.4%, p = 0.003) and skeletal muscle mass (-37%, p = 0.006). Moreover, cachectic mice had elevated CD45+CD11b+Ly6g+ neutrophils from non-tumor bearing controls (128%, p = 0.016) and elevated CD45+CD206+MHCII- profibrotic macrophages compared to weight stable (43%, p = 0.014) and non-tumor bearing controls (59%, p = 0.002) with thickening of the ECM via electron microscopy analysis on decellularized skeletal muscle. CONCLUSIONS: These data highlight the changes to muscle immune cells in the progression of fibrosis and excessive ECM deposition in cancer cachexia. Targeting pro-fibrotic immune cells may represent a promising therapeutic approach to mitigate skeletal muscle wasting and dysfunction in cancer cachexia. Supported by: F99CA294251 (TDC), K99CA278691 (BNV), U01CA272977 (EAM)