CRC genome-driven metabolic reprogramming and immune microenvironment remodeling

Abstract

Abstract Background Colorectal cancer is a global digestive tract malignancy closely tied to microsatellite instability (MSI). MSI stems from DNA mismatch repair issues, categorized as MSI-High (MSI-H), MSI-Low (MSI-L), or Stable (MSS). Tailoring treatments based on MSI status is vital. MSI-H tumors, with high mutation and neoantigen loads, respond well to immune checkpoint inhibitors (ICIs). However, some MSI-H tumors display resistance due to complex factors like the tumor microenvironment, signaling pathways, immune cells, and checkpoint molecules. Methods Through the analysis of CRC genomic data, we identified the key genomic events that drive MSI. At the same time, through transcriptome analysis, we discovered the key genes. Results We performed a differential analysis between MSI-H and MSS/MSI-L and found that signaling pathways involved in lipid and hormone metabolism were significantly inhibited, including cholesterol homeostasis and hormone metabolism processes. At the same time, immune-related pathways were significantly activated. We identified genes associated with MSI-H, such as FAT4, BRAF, APC, and TTN, that were mutated at a higher frequency and number in MSI-H patients, thereby affecting tumor initiation, progression, and treatment response. These genes participate in different signaling pathways, such as Wnt/β-catenin pathway, MAPK pathway, PI3K/AKT pathway, etc. Conclusion This study reveals the presence of an active immune response in MSI-H tumors along with reduced levels of lipid metabolism and abnormal pathway phenotypes related to the proliferation and migration of Wnt/β-catenin and the MAPK pathway.