Investigating the contribution of aberrant sphingosine 1-phosphate signalling to the pathogenesis of diffuse large B-cell lymphoma

Lupino, Lauren (2017). Investigating the contribution of aberrant sphingosine 1-phosphate signalling to the pathogenesis of diffuse large B-cell lymphoma. University of Birmingham. Ph.D.

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Abstract

There is an increasing body of evidence indicating an important role for the bioactive signalling lipid S1P (sphingosine 1-phosphate) in cancer. Sphingosine kinase-1 (SPHK1), one of the enzymes responsible for the synthesis of S1P, is reported to be overexpressed in many cancer types; in many cases correlating with increased tumour grade and reduced patient survival. However, the expression of SPHK1, and how it might contribute to lymphomagenesis, has not previously been explored in diffuse large B-cell lymphoma (DLBCL).
In chapter 3, I show that SPHK1 overexpression in DLBCL correlates with the expression of known tumour-angiogenic genes. I also describe the characterisation of human umbilical vein endothelial cells (HUVEC) as an in vitro model with which to study the impact of S1P on the endothelial cell transcriptome and to explore the extent to which these changes can be observed in primary DLBCL.
In chapter 4, I explore the effects of S1P on the transcription of endothelial cells with a focus on genes associated with leukocyte recruitment. I confirm the S1P-induced upregulation of chemokines and adhesion molecules in HUVEC and show that SPHK1 expression correlates with the expression of stromal cell gene signatures in primary DLBCL.
Finally, in chapter 5, I show that I can inhibit S1P-induced signalling in HUVEC with Sphingomab, a monoclonal antibody against S1P. Additionally, I validate the A20 syngeneic model of lymphoma as a relevant system which could be used to study the potential therapeutic targeting of SPHK1-S1P signalling in DLBCL.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):