Investigating the role of senescence biomarkers in colorectal cancer heterogeneity by bulk and single-cell RNA sequencing

Abstract

Abstract Colorectal cancer (CRC) is one of most common tumors worldwide, causing a prominent global health burden. Cell senescence is a complex physiological state, characterized by proliferation arrest. Here, we investigated the role of cellular senescence in the heterogeneity of CRC. Based on senescence-associated genes, CRC samples were classified into different senescence patterns with different survival, cancer-related biological processes and immune cell infiltrations. A senescence-related model was then developed to calculate the senescence-related score to comprehensively explore the heterogeneity of each CRC sample such as stromal activities, immunoreactivities and drug sensitivity. Single-cell analysis revealed there were different immune cell infiltrations between low and high senescence-related model genes enrichment groups, which was confirmed by multiplex immunofluorescence staining. Pseudotime analysis indicated model genes play a pivotal role in the evolution of B cells. Besides, intercellular communication modeled by NicheNet showed tumor cells with higher enrichment of senescence-related model genes highly expressed CXCL2/3 and CCL3/4, which attracted immunosuppressive cell infiltration and promoted tumor metastasis. Finally, top 6 hub genes were identified from senescence-related model genes by PPI analysis. And RT-qPCR revealed the expression differences of hub genes between normal and CRC cell lines, indicating to some extent the clinical practicability of senescence-related model. To sum up, our study explores the impact of cellular senescence on the prognosis, TME and treatment of CRC based on senescence patterns. This provides a new perspective for CRC treatment.

Keywords

• Colorectal cancer
• Cellular senescence
• Tumor microenvironments
• Immunotherapy
• Single-cell RNA sequencing