From heterogeneity to mechanism: a systems-level analysis pinpoints the S100A8/A9 axis in colorectal cancer.

BACKGROUND

The functional roles of the S100 protein family in colorectal cancer (CRC) are enigmatic, marked by widespread dysregulation but limited prognostic utility. This heterogeneity obscures their potential as therapeutic targets.

METHODS

We employed a multi-omics strategy to deconstruct this complexity, integrating bulk transcriptomics (TCGA), large-scale single-cell RNA-seq atlases, and machine learning-based prioritization. Cell-type-specific expression patterns were contextualized using the spatial annotation of cell origins available within the Pan-GI Cell Atlas. Key findings were validated experimentally via qRT-PCR in a 30-patient cohort and functionally assessed using in vitro assays.

RESULTS

While 17 S100 genes were differentially expressed in bulk tumor tissue, they lacked collective prognostic power. Single-cell analysis resolved this paradox, revealing that the expression of key alarmins S100A8 and S100A9 is not tumor-intrinsic but is highly concentrated in tumor-infiltrating myeloid cells. This myeloid-specific signature was associated with high-grade disease and progressively increased from polyps to tumors. We experimentally validated that S100A8 and S100A9 mRNA levels are significantly elevated in CRC tissues versus adjacent normal controls (S100A8, p = 0.004; S100A9, p = 0.012). Functionally, recombinant S100A8 and S100A9 acted as drivers of inflammation, directly inducing a pro-inflammatory cascade including NF-κB, IL-6, and IL-8 in CRC cells.

CONCLUSIONS

Our findings clarify the S100 family's role in CRC, identifying the myeloid-derived S100A8 and S100A9 axis as a key amplifier of the pro-tumorigenic inflammatory microenvironment. This axis represents a critical nexus between innate immunity and carcinogenesis, offering a promising target for novel anti-inflammatory or immunomodulatory therapies in CRC.