E‐selectin affinity glycoproteomics reveals neuroendocrine proteins and the secretin receptor as a poor‐prognosis signature in colorectal cancer

Abstract

Colorectal cancer (CRC) cells express sialylated Lewis antigens (sLe), crucial for metastasis via E‐selectin binding. However, these glycoepitopes lack cancer specificity, and E‐selectin‐targeted glycoproteins remain largely unknown. Here, we established a framework for identifying metastasis‐linked glycoproteoforms. More than 70% of CRC tumors exhibited overexpression of sLeA/X, yet without discernible associations with metastasis or survival. However, The Cancer Genome Atlas (TCGA) analysis unveiled differing expression patterns of sLeA/X‐related glycogenes correlating with disease severity, indicating context‐dependent regulation by distinct glycosyltransferases. Deeper exploration of metastatic tumor sialoglycoproteome identified nearly 600 glycoproteins, greatly expanding our understanding of the metastasis‐related glycoproteome. These glycoproteins were linked to cell adhesion, oncogenic pathways, and neuroendocrine functions. Using an in‐house algorithm, the secretin receptor (SCTR) emerged as a top‐ranked targetable glycoprotein. Tumor screening confirmed SCTR's association with poor prognosis and metastasis, with N‐glycosylation adding cancer specificity to this glycoprotein. Prognostic links were reinforced by TCGA‐based investigations. In summary, SCTR, a relatively unknown CRC glycoprotein, holds potential as a biomarker of poor prognosis and as an E‐selectin ligand, suggesting an unforeseen role in disease dissemination. Future investigations should focus on this glycoprotein's biological implications for clinical applications.