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

Lauren Lupino, Tracey Perry, Sandra Margielewska, Robert Hollows, Maha Ibrahim, Matthew Care, Jeremy Allegood, Reuben Tooze, Roger Sabbadini, Gary Reynolds, Roy Bicknell, Zbigniew Rudzki, Ye Lin Hock, Ulises Zanetto, Wenbin Wei, William Simmons, Sarah Spiegel, Ciaran B J Woodman, Martin Rowe, Katerina VrzalikovaPaul G Murray

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)2884-2897
Number of pages14
JournalLeukemia
Volume33
Issue number12
Early online date16 May 2019
DOIs
Publication statusPublished - Dec 2019

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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