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Updated: Jul 3, 2026
Heterogeneity Mapping of Protein Expression in Tumors using Quantitative Immunofluorescence
Published on: October 25, 2011
From heterogeneity to mechanism: a systems-level analysis pinpoints the S100A8/A9 axis in colorectal cancer
Hamideh Raeisi1, Mahsa Saeedi Niasar2, Ehsan Nazemalhosseini Mojarad1
1Gastroenterology and Liver Diseases Research Centre, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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.
Insights
The S100 protein family
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- The S100 protein family's role in colorectal cancer (CRC) is unclear, despite widespread dysregulation.
- Their complex expression patterns limit their use as prognostic markers or therapeutic targets.
Purpose of the Study:
- To elucidate the functional roles of S100 proteins in colorectal cancer.
- To resolve the heterogeneity of S100 protein expression and identify potential therapeutic strategies.
Main Methods:
- Integrated multi-omics data including bulk transcriptomics (TCGA) and single-cell RNA-seq.
- Utilized machine learning for prioritization and spatial annotation from the Pan-GI Cell Atlas.
- Validated findings via qRT-PCR and in vitro functional assays.
Main Results:
- Seventeen S100 genes were differentially expressed in bulk CRC tissue but lacked prognostic value.
- Single-cell analysis revealed S100A8 and S100A9 expression is concentrated in myeloid cells, not tumor cells.
- Myeloid S100A8/S100A9 expression correlated with high-grade CRC and drove inflammation by inducing NF-κB, IL-6, and IL-8.
Conclusions:
- The S100A8/S100A9 axis, originating from myeloid cells, amplifies the pro-tumorigenic inflammatory microenvironment in CRC.
- This axis links innate immunity to carcinogenesis, presenting a potential therapeutic target for anti-inflammatory or immunomodulatory treatments in CRC.
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