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Dual roles of ANXA7 in the early diagnosis and prognostic prediction of colorectal cancer: insights from serum exosome proteomics and single-cell transcriptomics
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DOI：10.1186/s12951-026-04915-z.png)
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Abstract
En 中文
Colorectal cancer (CRC) develops over 10–15 years from normal mucosa to advanced adenoma (AA) and invasive carcinoma; however, noninvasive biomarkers capable of detecting premalignant lesions and predicting the patient prognosis are still urgently needed. Circulating small extracellular vesicles (sEVs, exosomes) are nanoscale lipid bilayer carriers that are stably enriched in body fluids and serve as ideal liquid biopsy substrates for tumor molecular profiling. Nevertheless, most existing exosomal biomarker studies adopt binary case‒control designs, lack sequential adenoma‒carcinoma cohorts, and rarely combine exosomal proteomics with single-cell transcriptomics to trace the cellular origins of the biomarkers or construct paired diagnostic‒prognostic models. We integrated EXODUS rapid sEV isolation technology with 4D-DIA quantitative proteomics to profile serum exosomal proteomes across four sequential cohorts: healthy controls (NCs), patients with AA, patients with early CRC (ECRC), and patients with advanced CRC. Time series clustering and cross-cohort differential screening identified annexin A7 (ANXA7) as a continuously upregulated exosomal protein that accompanies malignant transformation in CRC. Western blotting and commercial ELISA verified the progressive increase in circulating sEV-ANXA7 levels, while tissue immunohistochemistry further confirmed the increase in ANXA7 expression from normal epithelium to adenoma and carcinoma epithelium. A single ROC curve analysis demonstrated that serum sEV-ANXA levels achieved an AUC of 0.821 for distinguishing healthy individuals from those with high-risk advanced adenomas. The combination of sEV-ANXA7 levels with the levels of the traditional markers CEA and CA199 significantly improved the diagnostic accuracy for both premalignant and early CRC lesions. Single-cell transcriptomic mining of public CRC datasets revealed a unique ANXA7⁺ epithelial progenitor cell (EPC) subpopulation, a distinct epithelial subset containing precancerous abnormal epithelial cells and early malignant epithelial cells with elevated malignant transformation potential, which was highly enriched in tumor tissues, which featured elevated stemness signatures, increased malignant scores, and the activation of ferroptosis and the P53 signaling pathway. The results of the CellChat analysis further revealed that ANXA7⁺ EPCs mediate tumor immune escape via CD8A–CEACAM5 ligand–receptor crosstalk with T cells. In vitro CCK-8 and EdU functional assays confirmed that ANXA7 markedly accelerated the proliferation of HCT116 and SW480 CRC cells. Based on the overlapping upregulated genes from ANXA7-high bulk tumors and ANXA7⁺ EPC subsets, we established a 12-gene LASSO prognostic signature, which exhibited robust performance in predicting 1–5-year survival (AUC > 0.68) of patients in both TCGA training cohort and the independent GEO validation cohort. Collectively, the results of this multiomics study reveal serum exosomal ANXA7 as a dual-function nanovesicle biomarker for early adenoma screening and the prognostic risk stratification of CRC and reveal the oncogenic ANXA7⁺ epithelial progenitor cell population that drives malignant colorectal progression. Our work provides translational evidence and theoretical basis for the development of exosome-based noninvasive liquid biopsy strategies and targeted therapeutic interventions against CRC.
Keywords:
Serum small extracellular vesicles
4D-DIA proteomics
Single-cell transcriptomics
ANXA7
Advanced adenoma
Colorectal cancer
Diagnostic and prognostic model
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