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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

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

  • Zhiwei Zhang1,2
  • Zhiyuan Gong1,2
  • Akao Zhu1,2
  • Cao Chen1,2
  • Yeting Hu1
  • Jian Wang1
  • Lifeng Sun1
  1. 1Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
  2. 2Department of Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026integrated,
  title = {{Integrated Multi-Omic Analysis of Paired Primary and Peritoneal Metastatic Tumors Reveals GPAA1 as a Therapeutic Target in Colorectal Cancer}},
  author = {Zhiwei Zhang and Zhiyuan Gong and Akao Zhu and Cao Chen and Yeting Hu and Jian Wang and Lifeng Sun},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27209106},
  url = {https://www.mdpi.com/1422-0067/27/20/9106},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Integrated Multi-Omic Analysis of Paired Primary and Peritoneal Metastatic Tumors Reveals GPAA1 as a Therapeutic Target in Colorectal Cancer
AU  - Zhiwei Zhang
AU  - Zhiyuan Gong
AU  - Akao Zhu
AU  - Cao Chen
AU  - Yeting Hu
AU  - Jian Wang
AU  - Lifeng Sun
PY  - 2026
DA  - 2026/10/14
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27209106
UR  - https://www.mdpi.com/1422-0067/27/20/9106
AB  - 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.
SN  - 1422-0067
ER  -