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Targeting Siglec-engaging immunosuppressive sialoglycans to suppress prostate cancer bone metastasis
Ziqian Peng1, Kirsty Hodgson1, Matthew Fisher2
1Newcastle University Centre for Cancer, Newcastle University Institute of Biosciences, Newcastle, UK.
Background:
Prostate cancer is a leading cause of male cancer-related deaths over the age of 50. New treatment options are urgently needed, especially for prostate tumours that have spread to bone. Targeting aberrant sialylation holds substantial potential for the development of new therapeutics but is relatively unexplored in the context of prostate cancer.
Methods:
Here, using high-affinity Siglec-based sialoglycan-binding reagents (HYDRA) for immunohistochemistry, we quantify tumour sialoglycans in tissues representing the full clinical heterogeneity of prostate cancer. Using immunofluorescence, we profile Siglec receptors in prostate tumours, and using syngeneic mouse models, we evaluate an engineered dual-action sialidase (E-612) as a treatment for prostate cancer bone metastasis.
Results:
We find that sialoglycans that can engage Siglec-3 (CD33), Siglec-7 and Siglec-9 are upregulated in bone metastatic prostate cancer and show that sialoglycan ligands for Siglec-7 and -9 correlate with poorer patient prognosis. Furthermore, we reveal Siglec receptors and Siglec ligands are co-expressed by immune cells in prostate-derived tumours growing in bone. Indicating the Siglec-sialoglycan axis is clinically actionable in prostate cancer, we show systemic therapy with E-612 can suppress the growth of tumours, increase immune cell infiltration and prolong survival times of mice with bone metastasis.
Conclusions:
Our findings identify a novel mechanism involving Siglec-engaging sialoglycans in driving the growth of prostate cancer bone metastasis and demonstrate that targeting this axis using an engineered sialidase can impede lethal prostate cancer progression.
Insights
Aberrant sialylation drives prostate cancer bone metastasis. Targeting this pathway with engineered sialidase (E-612) shows promise for treating advanced prostate cancer.
Area of Science:
- Oncology
- Immunology
- Glycobiology
Background:
- Prostate cancer is a major cause of cancer death in men over 50.
- Metastatic prostate cancer, particularly bone metastasis, requires novel therapeutic strategies.
- Aberrant sialylation is a potential therapeutic target in cancer, but its role in prostate cancer is underexplored.
Purpose of the Study:
- To investigate the role of sialylation in prostate cancer bone metastasis.
- To evaluate the therapeutic potential of targeting the Siglec-sialoglycan axis in prostate cancer.
Main Methods:
- Utilized high-affinity Siglec-based reagents (HYDRA) for sialoglycan quantification in diverse prostate cancer tissues.
- Employed immunofluorescence to profile Siglec receptor expression in tumors.
- Assessed an engineered sialidase (E-612) in syngeneic mouse models of prostate cancer bone metastasis.
Main Results:
- Sialoglycans engaging Siglec-3, -7, and -9 were upregulated in bone metastatic prostate cancer.
- Siglec-7 and -9 ligands correlated with poorer patient prognosis.
- Engineered sialidase (E-612) suppressed tumor growth, enhanced immune cell infiltration, and prolonged survival in mouse models.
Conclusions:
- Identified a novel mechanism where Siglec-engaging sialoglycans promote prostate cancer bone metastasis.
- Demonstrated that targeting the Siglec-sialoglycan axis with engineered sialidase impedes lethal prostate cancer progression.
