Marco Arese, Ph.D.
Associate Professor of Biochemistry
University of Torino, School of Medicine
Over the past few years, we have pursued and succeeded in the search for the function of two synaptic proteins in the vascular system and tumor cells. The following are the main achievements: We have demonstrated that Nrxns and Nlgns are produced and processed by endothelial and vascular smooth muscle cells throughout the vasculature. Moreover, they are dynamically regulated during vessel remodeling and form endogenous complexes in large vessels as well as in the brain. We used the chicken chorioallantoic membrane as a system to pursue functional studies and demonstrate that a monoclonal recombinant antibody against Nrxn inhibits angiogenesis, whereas exogenous Nlgn has a role in promoting angiogenesis. Finally, as an insight into the mechanism of action of beta-neurexin, we show that an anti-beta- Nrxn antibody influences vessel tone in isolated chicken arteries. To further investigate the Nrxn Nlgn role in vascular development we used zebrafish (Danio rerio) as a model system. We have shown that functional knockdown of Nrxn and Nlgn causes defects in sprouting angiogenesis and vascular remodeling. Next, we verified the presence of a functional interaction between Nrxn or Nlgn and the most studied angiogenic factor to date: VEGFA . Our data represent the first in vivo evidence of the role of Nrxn and Nlgn in embryonic blood vessels formation and provide important insights into their mechanism of action. In a separate set of experiments we focused on cancer biology and demonstrated that: (i) Nrxn is expressed by tumor blood vessels and tumor parenchyma in vivo; (ii) Nlgn protein expression is heavily downregulated during colorectal cancer progression. These data have been collected through biological analysis of human tissue samples obtained within IRCC and done in house, and consistently confirmed through data taken from public cancer gene expression databases (Oncomine, TCGA); (iii) Nlgn expression correlates with prostate cancer progression and hormone dependence (a collaboration with Prof Eva Corey, University of Washington, Seattle, WA)