Post-transcriptional regulation of angiogenesis

Angiogenesis (the formation of new blood vessels form from pre-existing vessels) is a hallmark of solid tumors allowing oxygen and nutrients to reach proliferating cancer cells and providing tumor cells with the metastatic route to colonize distant organs. Paradoxically, in contrast to the well-known transcriptional mechanisms that control angiogenesis, the information regarding the role of AS regulation during this process is very limited. This is very surprising since endothelial cells (ECs) of the tumor vasculature express a number of AS isoforms absent in adult tissues and some of them are investigated in clinical studies to develop antiangiogenic cancer treatments. However, the biological activity of most AS variants enriched in ECs – as well as the specific splicing factors responsible for their production – are still largely unknown. Since anti-angiogenic strategies so far have showed modest therapeutic effects, a better understanding of the molecular mechanisms, for instance AS regulation, that sustain growth of tumor vessels will be crucial to identify novel and more efficient anti-angiogenic therapies for cancer treatment.

In the past, we discovered that Nova2, a tissue-restricted AS factor previously identified and characterized for its important functions in the neurons of the central nervous system, is also expressed in the vascular endothelium and plays a relevant role in vascular morphogenesis. From genome-wide approaches and histological analysis of Nova2 mutant animals generated through CRISPR/Cas9 technology, we demonstrated that Nova2 acts as a post-transcriptional regulator of the molecular mechanisms involved in the establishment of EC polarity and in the organization of the vascular lumen during blood vessels development. Very recently, we found Nova2 is upregulated in tumor vasculature, where high Nova2 expression correlates with shorter overall survival of cancer patients.

Our main interests are:
1) to identify new transcripts generated through Nova2-mediated AS regulation in ECs;
2) to characterize the function of some protein isoforms generated by Nova2-mediated AS in ECs;
3) to study the role of Nova2 in tumor vessels;
4) identify AS isoforms specifically expressed in tumor vasculature as a possible prognostic or therapeutic targets.