RESERACH SUMMARY

We focus on the study of APRIL (a proliferation-inducing ligand), a member of the TNF family proteins named for its ability to stimulate the proliferation of tumour cells in vitro. APRIL binds to two known TNF receptors, TACI and BCMA. In addition, APRIL binds to heparan sulphate proteoglycans (HSPG), although the biological significance is not yet clear. APRIL is expressed by several cell types (dendritic cells, macrophages, epithelial cells, osteoclasts) and secreted as a soluble factor.

APRIL is known to enhance B cell proliferation and cell survival; it also enhances T independent humoural responses and promotes immunoglobulin class-switch recombination to IgG and IgA. Altered APRIL expression has been detected in pathological situations such as autoimmunity and cancer. We described that APRIL transgenic mice develop lymphoid tumours that originate from the expansion of peritoneal B cells. Tumours in these mice resemble human chronic lymphocytic leukaemia (CLL), and our analysis of CLL patient sera shows an increase in circulating APRIL levels that correlates with reduced overall survival. In these B cell malignancies, APRIL activates NFkappaB transcription factor, promotes tumour cell survival and protects cells from apoptosis.

Our main goal is to dissect APRIL function in the immune system and in pathological conditions. One research line studies the relevance of APRIL in epithelial breast cancer, using cell lines and mouse models. We detected high APRIL mRNA levels in 30% of the human primary breast tumours analysed and found that APRIL protein is expressed in various human breast cancer cell lines and promotes their proliferation. We identified molecules that stimulate APRIL secretion in these cancer cells and characterised the signalling transduction pathways activated by the cytokine. We also generated the MMTV-neu/APRIL double transgenic mouse and used syngeneic tumour transplant models in APRIL-Tg and APRIL-KO mice to study the influence of APRIL in epithelial tumour development in vivo. We are also exploring the potential clinical use of APRIL and analysing its expression in human solid primary tumours.

Another line of research uses mouse models and human samples to focus on autoimmune diseases (RA, SLE) and B cell deficiencies (XLA). We are examining the cell types responsible for APRIL/BAFF secretion and the factors that regulate it, the effects mediated by APRIL/BAFF, the target cells involved and the signalling pathways activated.

Finally, we are working on the generation of APRIL antagonist molecules that effectively block this cytokine as a strategy for blocking tumour development.