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

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.