Siglec-engaging immunosuppressive sialoglycans are upregulated in prostate cancer and are targetable to suppress bone metastasis

作者：Ziqian Peng, Kirsty Hodgson, Matthew Fisher, Shenglin Mei, Margarita Orozco‐Moreno, Lizhi Cao, Michael Kemp, Wayne Gatlin, Louisa Donald, F. Zeng, Michelle A. Lawson, Dániel Ungár, David B. Sykes, David J. Elliott, Li Peng, Ben Schumann, Ning Wang, Jennifer Munkley · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.11.12.687981 · 被引用次数：3 · 研究领域：Glycosylation and Glycoproteins Research、Proteoglycans and glycosaminoglycans research、Bone and Dental Protein Studies

Abstract Prostate cancer is a leading cause of male cancer-related deaths over the age of 50. New treatment options for prostate cancer are urgently needed, especially for tumours that have spread to bone. Aberrant sialylation holds substantial potential for the discovery of new therapeutic targets but has remained relatively unexplored in the context of prostate cancer, primarily due to the lack of reliable reagents for detecting tumour sialoglycans in clinical tissue. Here, we address this knowledge gap using high-affinity Siglec-based sialoglycan-binding reagents (HYDRAs) to quantify tumour sialoglycans in tissues representing the full clinical heterogeneity of prostate tumours. Using HYDRA immunohistochemistry, we show that sialoglycans that can engage Siglec-3, -7, and -9 are upregulated in primary prostate cancer tissue and sialoglycan ligands for Siglec-7 correlate with prostate cancer bone metastasis and poorer patient prognosis. Analysis of prostate-derived tumours growing in bone reveals Siglec receptors are expressed by immune cells in the bone metastatic tumour microenvironment, suggesting that this axis may play a role in immune cell functions in bone metastatic prostate cancer. Indicating this is clinically actionable, an engineered bisialidase (E-612) can effectively strip Siglec ligands from prostate cancer cells and prolong survival times of mice with bone metastasis. Our findings identify a novel mechanism involving Siglec-engaging sialoglycans in driving th...