Adam Pierre, Salée Catherine, Quesada Calvo Florence, Lavergne Arnaud, Merli Angela-Maria, Massot Charlotte, Blétard Noëlla, Somja Joan, Baiwir Dominique, Mazzucchelli Gabriel, Coimbra Marques Carla, Delvenne Philippe, Louis Edouard, Meuwis Marie-Alice
Laboratory of Translational Gastroenterology, GIGA Institute, University of Liège, 4000 Liège, Belgium.
GIGA Bioinformatics, GIGA Institute, University of Liège, 4000 Liège, Belgium.
Int J Mol Sci. 2025 Jul 31;26(15):7401. doi: 10.3390/ijms26157401.
Accounting for 15-30% of colorectal cancer cases, the serrated pathway remains poorly characterized compared to the adenoma-carcinoma sequence. It involves sessile serrated lesions as precursors and is characterized by BRAF mutations (BRAF), CpG island hypermethylation, and microsatellite instability (MSI). Using label-free proteomics, we compared normal tissue margins from patients with diverticular disease, sessile serrated lesions, low-grade adenomas, and high-grade adenomas. We identified S100A14 as significantly overexpressed in sessile serrated lesions compared to low-grade adenomas, high-grade adenomas, and normal tissues. This overexpression was confirmed by immunohistochemical scoring in an independent cohort. Gene expression analyses of public datasets showed higher S100A14 expression in BRAF-mutated and MSI-H colorectal cancers compared to microsatellite stable BRAF tumors. This finding was confirmed by immunohistochemical scoring in an independent colorectal cancer cohort. Furthermore, single-cell RNA sequencing analysis from the Human Colon Cancer Atlas revealed that S100A14 expression in tumor cells positively correlated with the abundance of tumoral CD8 cytotoxic T cells, particularly the CD8 CXCL13 subset, known for its association with a favorable response to immunotherapy. Collectively, our results demonstrate for the first time that S100A14 is a potential biomarker of serrated neoplasia and further suggests its potential role in predicting immunotherapy responses in colorectal cancer.
锯齿状途径占结直肠癌病例的15%-30%，与腺瘤-癌序列相比，其特征仍不明确。它以无蒂锯齿状病变为前驱病变，其特征为BRAF突变（BRAF）、CpG岛高甲基化和微卫星不稳定性（MSI）。我们使用无标记蛋白质组学方法，比较了憩室病患者、无蒂锯齿状病变、低级别腺瘤和高级别腺瘤患者的正常组织边缘。我们发现，与低级别腺瘤、高级别腺瘤和正常组织相比，S100A14在无蒂锯齿状病变中显著过表达。在一个独立队列中通过免疫组化评分证实了这种过表达。对公共数据集的基因表达分析显示，与微卫星稳定的BRAF肿瘤相比，BRAF突变和MSI-H结直肠癌中S100A14表达更高。在一个独立的结直肠癌队列中通过免疫组化评分证实了这一发现。此外，来自人类结肠癌图谱的单细胞RNA测序分析表明，肿瘤细胞中S100A14的表达与肿瘤性CD8细胞毒性T细胞的丰度呈正相关，特别是CD8 CXCL13亚群，该亚群因与免疫治疗的良好反应相关而闻名。总的来说，我们的结果首次证明S100A14是锯齿状肿瘤形成的潜在生物标志物，并进一步表明其在预测结直肠癌免疫治疗反应中的潜在作用。
