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Sialic acid blockade inhibits the metastatic spread of prostate cancer to bone.pdf (4.03 MB)

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

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posted on 2024-06-14, 08:41 authored by 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

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

Background

Methods

Findings

Interpretation

Funding

History

Author affiliation

College of Life Sciences Genetics & Genome Biology

Version

  • VoR (Version of Record)

Published in

eBioMedicine

Volume

104

Pagination

105163

Publisher

Elsevier BV

issn

2352-3964

eissn

2352-3964

Copyright date

2024

Available date

2024-06-14

Spatial coverage

Netherlands

Language

en

Deposited by

Mrs Louise Thompson

Deposit date

2024-06-10

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