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Lookup NU author(s): Dr Kirsty Hodgson, Maggie Orozco Moreno, Emily Archer Goode, Dr Rebecca Garnham, Karen Livermore, Laura WilsonORCiD, Dr Gerald Hysenaj, Rashi Krishna, Jess Peng, Adam Duxfield, Dr Ella Dennis, Professor Rakesh Heer, Professor David Elliott, Libby Scott, Dr Jennifer Munkley
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 The Author(s). 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.
Author(s): Hodgson K, Orozco-Moreno M, Goode EA, Fisher M, Garnham R, Beatson R, Turner H, Livermore K, Zhou Y, Wilson L, Visser EA, Pijnenborg JF, Eerden N, Moons SJ, Rossing E, Hysenaj G, Krishna R, Peng Z, Nangkana KP, Schmidt EN, Duxfield A, Dennis EP, Heer R, Lawson MA, Macauley M, Elliott DJ, Bull C, Scott E, Boltje TJ, Drake RR, Wang N, Munkley J
Publication type: Article
Publication status: Published
Journal: eBioMedicine
Year: 2024
Volume: 104
Print publication date: 01/06/2024
Online publication date: 20/05/2024
Acceptance date: 06/05/2024
Date deposited: 29/05/2024
ISSN (electronic): 2352-3964
Publisher: Elsevier BV
URL: https://doi.org/10.1016/j.ebiom.2024.105163
DOI: 10.1016/j.ebiom.2024.105163
Data Access Statement: The authors confirm that the data supporting the findings of this study are available within the article and its Supplementary materials.
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