Integrated Analysis of Tumor-Associated Macrophages and M2 Macrophages in CRC: Unraveling Molecular Heterogeneity and Developing a Novel Risk Signature

Abstract

Abstract Background: Emerging investigations have increasingly highlighted the critical role of tumor-associated macrophages (TAMs) and M2 macrophages in cancer development, progression, and metastasis, marking them as potential targets in various cancer types. The main objective of this research is to discover new biomarkers associated with TAM-M2 in colorectal cancer (CRC) by combining single-cell RNA sequencing and bulk RNA-seq data. Our objective is to dissect the molecular heterogeneity of CRC and develop a novel risk signature. Methods: By utilizing weighted gene co-expression network analysis (WGCNA), we acquired TAM-M2-associated genes by intersecting TAM marker genes obtained from scRNA-seq data with module genes of M2 macrophages derived from bulk RNA-seq data. We employed least absolute shrinkage and selection operator (LASSO) Cox analysis to select predictive biomarkers from these TAM-M2-related genes. Quantitative Polymerase Chain Reaction (qPCR) was employed to validate the mRNA expression levels of the genes identified in the screening. This led to the development of the TAM-M2-related signature (TAMM2RS). We also conducted immune landscape analysis across different risk groups. Results: The combination of scRNA-seq and bulk RNA-seq analyses yielded 377 TAM-M2-related genes. DAPK1, NAGK, and TRAF1 emerged as key prognostic genes in CRC, identified through LASSO Cox analysis. Utilizing these genes, we constructed and validated the TAMM2RS, demonstrating its effectiveness in predicting survival in CRC patients. Conclusion: Our research offers a thorough investigation into the molecular mechanisms associated with TAM-M2 macrophages in CRC and unveils potential therapeutic targets, offering new insights for treatment strategies in colorectal cancer.