Pavel Tolar

 

Cancers with a sweet tooth: probing the role of B cell receptor-lectin interactions in human lymphomas

Immune responses rely on somatic mutagenesis in B cells in order to generate the diversity of antibodies that can neutralise wide range of pathogens. Excessive mutagenesis, however, can also lead to malignant transformation of B cells into lymphomas. In some B cell lymphomas, the mutations target signalling pathways downstream of the B cell receptor (BCR), indicating that the tumours are driven by chronic BCR signalling. Such signalling is similar to that normally induced by antigens and represents a new therapeutic target in these diseases. Surprisingly, recent findings showed that in human follicular lymphoma, an indolent and incurable type of B cell lymphoma, the malignant B cells contain mutations that introduce unusual glycans into the antigen-binding site of their BCRs. It has been proposed, that the glycosylation is a means to initiate chronic BCR signalling by binding to endogenous lectins expressed in the tumour microenvironment. This idea is a new paradigm in how the BCR acts in human lymphomas and suggests that lectin-induced signalling is a novel target for therapeutic intervention in follicular lymphoma patients. However, how the BCR engages the lectins and how is the signalling harnessed for the growth of the tumour is not known.

The Tolar lab has a long-standing interest in the mechanisms, by which BCR signals are initiated, regulated and how they drive normal and pathological B cell responses. The project will investigate the molecular mechanisms of lectin-induced signalling in follicular lymphoma cells and the consequences of the signalling for the growth and survival of the tumour. The research will employ genetic manipulation of the BCR signalling pathway in human cells using CRISPR/Cas9 and visualisation of signalling dynamics using state-of-the-art live cell imaging. This project will be a collaboration with Graham Packham and Freda Stevenson at the University of Southampton with the aim to inform new therapeutic strategies targeting the lectin-BCR pathway to treat patients with follicular lymphoma. The position will thus provide a unique training opportunity linking expertise in basic mechanisms of B cell signalling with therapeutic targeting of human B cell cancers.

1. Nowosad, C. R., Spillane, K. M. and Tolar, P. (2016)
Germinal center B cells recognize antigen through a specialized immune synapse architecture.
Nature Immunology  17: 870-877. PubMed abstract

2. Linley, A., Krysov, S., Ponzoni, M., Johnson, P. W., Packham, G. and Stevenson, F. K. (2015)
Lectin binding to surface Ig variable regions provides a universal persistent activating signal for follicular lymphoma cells.
Blood 126: 1902-1910. PubMed abstract

3. Young, R. M., Shaffer, A. L., 3rd, Phelan, J. D. and Staudt, L. M. (2015)
B-cell receptor signaling in diffuse large B-cell lymphoma.
Seminars in hematology  52: 77-85. PubMed abstract