Tumor-muscle tissue crosstalk in cancer cachexia

• Grant number: 20/03854-4
• Support Opportunities: Regular Research Grants
• Duration: March 01, 2022 - February 28, 2025
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Convênio/Acordo: Universidad de Antioquia (UdeA)
• Principal Investigator: Robson Francisco Carvalho
• Grantee: Robson Francisco Carvalho
• Principal researcher abroad: Juan Camilo Calderon Velez
• Institution abroad: Universidad de Antioquia (UdeA), Colombia
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
• Associated researchers: Geysson Javier Fernandez Garcia ; Maeli Dal Pai

Abstract

Cachexia is a multifactorial syndrome highly associated with specific tumor types, but the causes of the variation in the prevalence and severity of cachexia are still unknown. Although circulating plasma mediators (soluble cachectic factors) derived from the tumor have been implicated with the pathogenesis of the syndrome, these associations were generally based on the plasma concentration and not on the gene expression profile of these cachectic factors in the tumor microenvironment (TME). The combinatory action of soluble mediators (cachexia-inducing factors) secreted by cancer and normal cells in the TME, including pro-inflammatory cytokines, contribute to systemic inflammation and act directly on skeletal muscle, inducing mass loss. Consequently, efforts to identify mediators and biomarkers have focused on plasma levels of these cachectic factors. However, it is not yet clear whether these factors circulating in the blood are derived from TME cells or the host, including molecules that are expressed and released by muscle cells. The expression profiling of these secreted factors and their receptors may also reveal cell-to-cell communication across multiple cell types and tissues that strictly governs the proper functioning of cells, and extensively relies on interactions between secreted ligands and cell-surface receptors. However, this intricated transcriptional reprogramming mediated by specific transcriptional activators and intercellular crosstalk involving ligandreceptor interactions between TME and skeletal muscle tissue is underexplored. The complex and specific tumor-host interactions affecting muscle function and physiology also have to be fully elucidated. With novel strategies to address this knowledge gap, we here propose a collaborative multi-center study to connect the expression profiling of secreted molecules by the tumor and skeletal muscle tissues during the development of cachexia in tumor mice model, and the potential "in vitro" effects of secreted molecules in gene expression programs in C2C12 muscle cells (Aims 1 to 3, at Sao Paulo State University, Brazil). Second, we will study the physiological effects of the secreted molecules on skeletal muscle contraction (Aims 3 to 5, at the University of Antioquia, Colombia). The impact of this project is to understand the effects of CIF on the molecular and physiological dynamics that underpin dysfunction in cachectic muscles. Together, these results can serve as a basis for the development of future therapeutic strategies aiming to minimize the loss of muscle mass and, thus, increasing survival and improving the quality of life of patients with cancer-associated cachexia. (AU)