Oncogene-Induced Senescence Transcriptomes Signify Premalignant Colorectal Adenomas

TL;DR

This study shows that signs of cellular aging called OIS are more active in early colorectal tumors than in later cancer stages, suggesting they may temporarily stop cancer growth.

Contribution

The study identifies OIS and SASP signatures as potential biomarkers for early colorectal cancer detection and progression.

Findings

OIS and SASP signatures were significantly enriched in adenomas compared to adenocarcinomas.

Senescence regulators and SASP factors were downregulated in adenocarcinomas, indicating reduced senescence signaling.

65% of patients showed higher OIS scores in adenomas, while SASP enrichment declined in 59–61% of cases.

Abstract

Background: Oncogene-induced senescence (OIS) is a tumor-suppressive mechanism that halts uncontrolled cell proliferation in premalignant lesions. Further investigation into its role in colorectal tumorigenesis is essential. We investigated the expression of OIS transcriptomic landscapes in premalignant colorectal adenomas and whether their resolution is part to adenoma-to-carcinoma progression. Methods: Using a publicly available gene expression dataset (GSE117606), we analyzed 66 paired (matched) adenoma–adenocarcinoma samples. Single-sample gene set enrichment analysis (ssGSEA) was performed to assess OIS and senescence-associated secretory phenotype (SASP) signatures, and differential gene expression analysis was conducted to examine key senescence-related genes. Results: OIS and SASP signatures were significantly enriched in adenomas compared to adenocarcinomas (p < 0.05). Pairwise comparisons confirmed that 65% of patients exhibited higher OIS scores in adenomas, while SASP enrichment declined in 59–61% of cases. Several senescence regulators (CDKN1A, CDKN2B, and E2F3), ECM remodeling genes (MMP10 and TIMP2), and NF-κB-driven SASP factors (CCL2, CXCL2, NFKB1, and NFKB2) were significantly downregulated in adenocarcinomas, indicating the resolution of senescence-associated inflammatory signaling during tumor progression. Conclusions: These findings support the predominance of OIS phenotypes in colorectal adenomas, suggesting their potential role as a temporary barrier to tumorigenesis in colorectal cancer.

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