Sialic acid blockade inhibits the metastatic spread of prostate cancer to bone

Kirsty Hodgson; Margarita Orozco-Moreno; Emily Archer Goode; Matthew Fisher; Rebecca Garnham; Richard Beatson; Helen Turner; Karen Livermore; Yuhan Zhou; Laura Wilson; Eline A Visser; Johan Fa Pijnenborg; Nienke Eerden; Sam J Moons; Emiel Rossing; Gerald Hysenaj; Rashi Krishna; Ziqian Peng; Kyla Putri Nangkana; Edward N Schmidt; Adam Duxfield; Ella P Dennis; Rakesh Heer; Michelle A Lawson; Matthew Macauley; David J Elliott; Christian Büll; Emma Scott; Thomas J Boltje; Richard R Drake; Ning Wang; Jennifer Munkley

doi:10.1016/j.ebiom.2024.105163

Sialic acid blockade inhibits the metastatic spread of prostate cancer to bone

EBioMedicine. 2024 May 20:104:105163. doi: 10.1016/j.ebiom.2024.105163. Online ahead of print.

Authors

Kirsty Hodgson¹, Margarita Orozco-Moreno¹, Emily Archer Goode¹, Matthew Fisher², Rebecca Garnham¹, Richard Beatson³, Helen Turner⁴, Karen Livermore¹, Yuhan Zhou², Laura Wilson⁵, Eline A Visser⁶, Johan Fa Pijnenborg⁷, Nienke Eerden⁸, Sam J Moons⁹, Emiel Rossing⁶, Gerald Hysenaj¹, Rashi Krishna¹, Ziqian Peng¹, Kyla Putri Nangkana¹, Edward N Schmidt¹⁰, Adam Duxfield¹¹, Ella P Dennis¹², Rakesh Heer¹³, Michelle A Lawson², Matthew Macauley¹⁰, David J Elliott¹, Christian Büll¹⁴, Emma Scott¹, Thomas J Boltje⁶, Richard R Drake¹⁵, Ning Wang¹⁶, Jennifer Munkley¹⁷

Affiliations

¹ Newcastle University Centre for Cancer, Newcastle University Institute of Biosciences, Newcastle upon Tyne NE1 3BZ, UK.
² The Mellanby Centre for Musculoskeletal Research, Division of Clinical Medicine, The University of Sheffield, Sheffield, UK.
³ Centre for Inflammation and Tissue Repair, UCL Respiratory, Division of Medicine, University College London (UCL), Rayne 9 Building, London WC1E 6JF, UK.
⁴ Cellular Pathology, The Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK.
⁵ Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Paul O'Gorman Building, Newcastle upon Tyne NE2 4HH, UK.
⁶ Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University, Nijmegen, the Netherlands.
⁷ GlycoTherapeutics B.V., Nijmegen, the Netherlands.
⁸ Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University, Nijmegen, the Netherlands; GlycoTherapeutics B.V., Nijmegen, the Netherlands.
⁹ Synvenio B.V., Nijmegen, the Netherlands.
¹⁰ Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
¹¹ Newcastle University Centre for Cancer, Newcastle University Institute of Biosciences, Newcastle upon Tyne NE1 3BZ, UK; International Centre for Life, Biosciences Institute, Newcastle University, Newcastle Upon Tyne NE1 3BZ, UK.
¹² International Centre for Life, Biosciences Institute, Newcastle University, Newcastle Upon Tyne NE1 3BZ, UK.
¹³ Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Paul O'Gorman Building, Newcastle upon Tyne NE2 4HH, UK; Department of Urology, Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE7 7DN, UK.
¹⁴ Biomolecular Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen, the Netherlands.
¹⁵ Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC, USA.
¹⁶ The Mellanby Centre for Musculoskeletal Research, Division of Clinical Medicine, The University of Sheffield, Sheffield, UK; Leicester Cancer Research Centre, Department of Genetics and Genome Biology, University of Leicester, LE2 7LX, UK. Electronic address: nw208@Leicester.ac.uk.
¹⁷ Newcastle University Centre for Cancer, Newcastle University Institute of Biosciences, Newcastle upon Tyne NE1 3BZ, UK. Electronic address: Jennifer.munkley@ncl.ac.uk.

Abstract

Background: Bone metastasis is a common consequence of advanced prostate cancer. Bisphosphonates can be used to manage symptoms, but there are currently no curative treatments available. Altered tumour cell glycosylation is a hallmark of cancer and is an important driver of a malignant phenotype. In prostate cancer, the sialyltransferase ST6GAL1 is upregulated, and studies show ST6GAL1-mediated aberrant sialylation of N-glycans promotes prostate tumour growth and disease progression.

Methods: Here, we monitor ST6GAL1 in tumour and serum samples from men with aggressive prostate cancer and using in vitro and in vivo models we investigate the role of ST6GAL1 in prostate cancer bone metastasis.

Findings: ST6GAL1 is upregulated in patients with prostate cancer with tumours that have spread to the bone and can promote prostate cancer bone metastasis in vivo. The mechanisms involved are multi-faceted and involve modification of the pre-metastatic niche towards bone resorption to promote the vicious cycle, promoting the development of M2 like macrophages, and the regulation of immunosuppressive sialoglycans. Furthermore, using syngeneic mouse models, we show that inhibiting sialylation can block the spread of prostate tumours to bone.

Interpretation: Our study identifies an important role for ST6GAL1 and α2-6 sialylated N-glycans in prostate cancer bone metastasis, provides proof-of-concept data to show that inhibiting sialylation can suppress the spread of prostate tumours to bone, and highlights sialic acid blockade as an exciting new strategy to develop new therapies for patients with advanced prostate cancer.

Funding: Prostate Cancer Research and the Mark Foundation For Cancer Research, the Medical Research Council and Prostate Cancer UK.

Keywords: Bone metastasis; Glycans; Prostate cancer; Sialic acid; Sialylation; Therapeutics.