In search of normality: looking for molecular strategies to repair cancer blood vessels

Defects in the adhesion of endothelial cells (ECs) to each other and to the extracellular matrix (ECM) are
primarily responsible for the structural and functional abnormalities characterizing blood vessels of most solid
tumors. In addition to promote tumor cell intravasation and metastatic dissemination, abnormal tumor blood
vessels hinder the effective delivery of therapies and decrease the efficacy of radiotherapy and
immunotherapy. The development of treatments aimed at normalizing the tumor blood vasculature is
therefore needed. To this aim, it is crucial to identify the signal transduction pathways that govern the
adhesion dynamics of ECs and are altered in the abnormal vasculature of tumors, to therapeutically target
them.
I will describe our contributions to identifying mechanisms that control the dynamics of the adhesion of
ECs to each other and to the ECM. In particular, we unveiled how a series of different secreted proteins and
their receptors, originally identified for their ability to control axonal guidance, control the conformational activation,
the endosomal traffic and adhesive function of integrins and VE-cadherin in cultured ECs. So far,
we have identified three extracellular ligands that are at different stage of in vitro or in vivo validation to
understand whether these molecules could be exploitable or not to help correcting tumor vascular
abnormalities.

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