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

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.

Does Siponimod Exert Direct Effects in the Central Nervous System?

“…Since peripheral immune cells (especially lymphocytes) do not play a role in organotypic slice culture models, this experimental setup has shown convincingly that siponimod can have beneficial effects in the context of MS by directly modulating the brain cell function. Accordingly, the protective effect of siponimod is not only limited to EAE but has also been observed in other models such as intracerebral hemorrhage [125], where it limits the formation of perihemorrhagic edema, and in experimental stroke [126], where it limits peripheral immune cell recruitment, as well as in a mouse model of diffuse large B-cell lymphoma [127].…”

Recent advances in the role of sphingosine 1‐phosphate in cancer

“…Interestingly, tumour angiogenesis meta-signature genes are enriched and correlated with SK1 mRNA expression in a meta-analysis of over 2000 cases of DLBCL (both cell of origin and stromal subtypes). Moreover, S1P induces angiogenic signalling and gene expression programmes that are common to the vasculature of SK1-expressing DLBCL tumours [38]. Therefore, the potential therapeutic benefit of S1P 1 agonists, competitive antagonists and functional antagonists may depend upon the cancer type and further research is warranted.…”

New Insights into Diffuse Large B-Cell Lymphoma Pathobiology

“…More recently, Lupino et al [ 107 ] demonstrated that the overexpression of SPHK1, one of the two isozymes responsible for the production of sphingosine-1 phosphate (SP1), a bioactive sphingolipid metabolite acting as a potent inducer of angiogenesis [ 108 ], correlates with an angiogenic transcriptional program in DLBCL.…”