Abstract 364: Multi-omics approaches revealed the involvement of immune cells in skeletal muscles of lung cancer cachexia mouse model

Abstract

Abstract Cancer-associated cachexia (CAC) is a multifactorial syndrome characterized by loss of body weight and skeletal muscle mass that cannot be fully recovered by nutritional support. It accounts for approximately 20 % of cancer-related deaths. However, there are no approved treatments for CAC yet. In order to better understand CAC, we wanted to apply the multi-omics approaches to simultaneously assess tumors and skeletal muscles in CAC mouse models. First, we established a lung cancer cachexia mouse model by orthotopic transplantation of KRAS-mutant lung cancer cells. Lung tumor-bearing mice developed cachexia at 7 weeks post injection, showing over 20 % of body weight loss and wasting of skeletal muscles and fats. The histological and immunoblotting analyses revealed degradation of gastrocnemius (GA) and tibialis anterior (TA) muscles in CAC group. Then, we performed the bulk RNA sequencing to assess transcriptomic changes in lung tumors and GA muscles of CAC mice. In lung tumors, genes associated to ATP metabolic process was upregulated. However, skeletal muscles of CAC mice showed upregulation of genes involved in protein degradation and immune responses, while genes related to energy metabolism were downregulated. Notably, the immunohistochemical staining revealed the increased numbers of infiltrating macrophages and CD8+ T cells in skeletal muscles of CAC mice. These data suggest the involvement of immune cells in lung cancer-associated cachexia. To further identify the distinct immune cell populations involved in CAC, the single cell RNA sequencing was conducted using CD45+ immune cells infiltrated into GA muscles of CAC mice. The enrichment of natural killer cells, dendritic cells and T cells was detected in GA of CAC mice. Moreover, we confirmed the roles of the infiltrating immune cells by using the neutralizing antibodies in CAC mice. Taken together, these data suggest the involvement of the immune cells in the skeletal muscle wasting of CAC mice. These multi-omics approaches will shed light on development of therapeutics for cancer-induced cachexia. Citation Format: Se-Young Park, Bomi Kim, Myunggyo Lee, Haeseung Lee, Na-Young Song. Multi-omics approaches revealed the involvement of immune cells in skeletal muscles of lung cancer cachexia mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 364.