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.