Single-cell Transcriptional Profile of Cachexia-Mediating Factors: A Pan-Cancer Study

• Grant number: 23/03005-5
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: November 01, 2023
• End date: November 30, 2027
• Field of knowledge: Biological Sciences - Morphology - Histology
• Principal Investigator: Robson Francisco Carvalho
• Grantee: Victória Larissa Schimidt Camargo
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

Cancer-associated cachexia is a syndrome characterized by muscle mass and adipose tissue loss, which affects approximately 80% of advanced cancer patients. Circulating plasma mediators, called cachexia-mediating factors, have been implicated in the pathogenesis of the syndrome. These factors have a specific expression profile for each tumor type, and are associated with cachexia prevalence. However, it is necessary to elucidate which tumor microenvironment cells are responsible for the production of cachexia mediating factors. With single-cell RNA sequencing (scRNA-Seq), it is possible to explore the transcriptome of thousands of individual cells and characterize with high resolution the cellular and molecular heterogeneity of the tumor microenvironment, which may reveal biomarkers and mediators of the syndrome. The first objective of this project is to characterize the transcriptional profile of cachexia-mediating factors in all tumor microenvironment cells in 14 tumor types. The second objective is to identify new potential cachexia mediators, based on predictions of ligand-receptor interactions. For this, we will use the literature text mining tools Geneshot (https://maayanlab.cloud/geneshot/) and Open Targets (https://platform.opentargets.org/) to list relevant genes associated with cachexia in cancer, including possible therapeutic targets. The listed genes will be compared with the list of genes of the secretome, obtained by The Human Protein Atlas (https://www.proteinatlas.org/humanproteome/secretome) to generate a list of genes cachexia-mediating factors. ScRNA-seq data will be used to characterize the transcriptional profile of cachexia-mediating factors in the tumor microenvironment of 14 tumor types. The scRNA-seq data will be obtained from the Curated Cancer Cell Atlas database (https://www.weizmann.ac.il/sites/3CA/), which has scRNA-seq data from 2,310,177 cells, 71 studies , 1375 samples uniformly collected and processed. Gene expression data will be used to predict ligand (tumor cell) and receptor (muscle and adipose tissue) interactions. For validation, we will evaluate the ability of selected ligands to induce C2C12 muscle cell atrophy. Validations regarding adipose tissue will be done in collaboration with others researchers. Our results will generate a biological dimension of potentially useful ligand-receptor interactions to explain key molecular changes in cancer-associated cachexia. Identifying a profile of mediating factors of cell-specific cachexia, at the single-cell level, in different types of tumors, may help in the development of targeted therapies to treat types of cancers highly associated with the syndrome. This, in turn, may increase survival and improve the quality of life of patients with cancer-associated cachexia.