Scholarlink

Background <p>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.</p> Methods <p>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.</p> Results <p>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 <i>S100A8</i> and <i>S100A9</i> 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 <i>S100A8</i> and <i>S100A9</i> mRNA levels are significantly elevated in CRC tissues versus adjacent normal controls (S100A8, <i>p</i> = 0.004; S100A9, <i>p</i> = 0.012). Functionally, recombinant S100A8 and S100A9 acted as drivers of inflammation, directly inducing a pro-inflammatory cascade including <i>NF-κB</i>, <i>IL-6</i>, and <i>IL-8</i> in CRC cells.</p> Conclusions <p>Our findings clarify the S100 family’s role in CRC, identifying the myeloid-derived <i>S100A8</i> and <i>S100A9</i> 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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月1日

查看全文
  • Hamideh Raeisi,
  • Mahsa Saeedi Niasar,
  • Ehsan Nazemalhosseini Mojarad,
  • Nafiseh Erfanian,
  • Binazir Khanabadi,
  • Samira Saghafi,
  • Hossein Safarpour,
  • Amir Sadeghi

摘要

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.