WNT signalling affects cell migration, invasion and the lymphoma-endothelial interplay in Hodgkin Lymphoma

by Franziska Linke
Doctoral thesis
Date of Examination:2016-06-13
Date of issue:2016-06-23
Advisor:Prof. Dr. Dieter Kube
Referee:Prof. Dr. Holger Bastians
Referee:Prof. Dr. Henning Urlaub
Persistent Address: http://dx.doi.org/10.53846/goediss-5710

 

 

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Abstract

English

Classical Hodgkin Lymphoma (cHL) comprises a unique cancer where the microenvironment accounts for 99 % of the whole tumour mass. In cHL dissemination involves functionally neighbouring lymph nodes but the underlying mechanisms for the spread of lymphoma cells are poorly understood. This thesis aims at characterizing cHL cell migration, invasion and pro-angiogenic properties as well as at identifying the underlying oncogenic pathways. Herein, it is shown that cHL cell migration, invasion and adhesion depend on autocrine WNT signalling as revealed by the inhibition of WNT secretion with porcupine inhibitors Wnt-C59/IWP-2 but also by targeting canonical WNT signalling. Time-lapse studies identified an amoeboid type of cell migration modulated by WNT5A as well as by lymphocyte enhancer binding factor 1 (LEF-1) and β-catenin in a 3D cell culture model. Application of recombinant WNT5A, WNT5A overexpression and WNT5A receptor binding inhibition by Box5 affected cHL cell migration. Among the diverse WNT pathways, the WNT5A-FZD5-DVL3-RHOA cascade and basal canonical WNT signalling are regulators of cHL cell motility. In addition to these mechanistic insights into the in vitro role of WNTs, global gene expression data revealed increased WNT5A and LEF-1 expression in primary cHL cells in comparison to normal B-cell subsets and other lymphomas. The pro-angiogenic potential of cHL cells was revealed by sprouting and vascular tube formation assays of endothelial cells. In that context, LEF-1 and β catenin regulated the secreted VEGFA levels of cHL cells. Importantly, VEGFA gene expression is prognostic for cHL. Furthermore, impaired WNT secretion or canonical WNT signalling as well as WNT5A stimulation had an impact on lymphoma development in the chick chorio-allantoic membrane (CAM) assay. The vasculature network was significantly reduced after inhibition of WNT secretion by Wnt-C59 or canonical WNT pathway inhibition. Therefore, a model is proposed where WNT signalling plays an important role in regulating cHL progression-associated processes.
Keywords: WNT; Hodgkin Lymphoma; Migration
 
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