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

Research output: Contribution to journalArticle

Authors

External organisations

  • Cancer Bioinfomatics Group, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
  • South Egypt Cancer Institute, Assiut University, Assiut, Egypt.
  • Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK Haematological Malignancy Diagnostic Service, Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK r.tooze@leeds.ac.uk.
  • Department of Biochemistry and Molecular Biology and Massey Cancer, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
  • Department of Biology, San Diego State University, San Diego, CA, USA.
  • Cancer Immunology and Immunotherapy Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.
  • Institutes of Cardiovascular Sciences and Biomedical Research, University of Birmingham, Birmingham, UK.
  • Department of Histopathology, Heartlands Hospital, Birmingham, UK.
  • Department of Histopathology, Walsall Manor Hospital, Walsall, UK.
  • Department of Histopathology, City Hospital, Birmingham, UK.
  • Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom.
  • Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK. k.vrzalikova@bham.ac.uk.
  • Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK. p.g.murray@bham.ac.uk.
  • Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 775 15 Olomouc, Czech Republic. p.g.murray@bham.ac.uk.

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.

Details

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

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