Sphingosine-1-phosphate signalling drives an angiogenic transcriptional programme in diffuse large B cell lymphoma.

Lupino, Lauren and Perry, Tracey and Margielewska, Sandra and Hollows, Robert and Ibrahim, Maha and Care, Matthew and Allegood, Jeremy and Tooze, Reuben and Sabbadini, Roger and Reynolds, Gary and Bicknell, Roy and Rudzki, Zbigniew and Lin Hock, Ye and Zanetto, Ulises and Wei, Wenbin and Simmons, William and Spiegel, Sarah and Woodman, Ciaran B J and Rowe, Martin and Vrzalikova, Katerina and Murray, Paul G (2019) Sphingosine-1-phosphate signalling drives an angiogenic transcriptional programme in diffuse large B cell lymphoma. Leukemia. ISSN 1476-5551. This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs

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Official URL: https://www.nature.com/articles/s41375-019-0478-9

Abstract

Although the over-expression of angiogenic factors is reported in diffuse large B-cell lymphoma (DLBCL), the poor response to anti-VEGF drugs observed in clinical trials suggests that angiogenesis in these tumours might be driven by VEGF-independent pathways. We show that sphingosine kinase-1 (SPHK1), which generates the potent bioactive sphingolipid sphingosine-1-phosphate (S1P), is over-expressed in DLBCL. A meta-analysis of over 2000 cases revealed that genes correlated with SPHK1 mRNA expression in DLBCL were significantly enriched for tumour angiogenesis meta-signature genes; an effect evident in both major cell of origin (COO) and stromal subtypes. Moreover, we found that S1P induces angiogenic signalling and a gene expression programme that is present within the tumour vasculature of SPHK1-expressing DLBCL. Importantly, S1PR1 functional antagonists, including Siponimod, and the S1P neutralising antibody, Sphingomab, inhibited S1P signalling in DLBCL cells in vitro. Furthermore, Siponimod, also reduced angiogenesis and tumour growth in an S1P-producing mouse model of angiogenic DLBCL. Our data define a potential role for S1P signalling in driving an angiogenic gene expression programme in the tumour vasculature of DLBCL and suggest novel opportunities to target S1P-mediated angiogenesis in patients with DLBCL.

Item Type: Article
Additional Information: This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs
Subjects: QZ Pathology. Oncology
Divisions: Clinical Support > Pathology
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Depositing User: Miss Emily Johnson
Date Deposited: 24 May 2019 14:13
Last Modified: 24 May 2019 14:13
URI: http://www.repository.heartofengland.nhs.uk/id/eprint/2106

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