Integrated Multi-Omic Analysis of Paired Primary and Peritoneal Metastatic Tumors Reveals GPAA1 as a Therapeutic Target in Colorectal Cancer

Peritoneal metastasis confers a dismal prognosis in colorectal cancer (CRC-PM), with median survival rarely exceeding 20 months. Here we employed multi-omic profiling to identify actionable drivers of CRC-PM. We performed whole-exome sequencing (WES) and label-free quantitative proteomics on 13 and 7 matched primary-peritoneal metastasis pairs, respectively. Public single-cell (GSE183916 and GSE132465) and spatial transcriptomic datasets (GSE225857) were integrated to dissect cellular heterogeneity. TCGA cohorts were used for survival analysis, and functional validation was performed in DLD1 cells. GPAA1, a catalytic subunit of the GPI transamidase complex, emerged as the most consistently upregulated protein in peritoneal metastases across discovery and validation proteomic cohorts. High GPAA1 expression correlated with shorter recurrence-free survival (HR = 1.72, p = 3.4 × 10−5). Single-cell analysis localized GPAA1 to malignant cells exhibiting oxidative phosphorylation and enhanced stromal crosstalk. GPAA1 overexpression promoted proliferation, migration, and EMT via AKT activation, whereas knockdown reversed these phenotypes. Our findings identify GPAA1 as a candidate driver of peritoneal metastasis in CRC, linking GPI anchor biosynthesis to metabolic reprogramming and AKT-mediated EMT. GPAA1 may serve as a prognostic marker in colorectal cancer.