Cell Adhesion Dynamics
Guido Serini, M.D. Ph.D.
Full Professor University of Torino Medical School
Grasping the molecular basis of cell adhesion dynamics to design effective ‘vascular normalizing’ drugs for anticancer therapy.
Tumor blood vessels are structurally and functionally aberrant, thus they hamper the delivery of anti-cancer drugs and cause hypoxia-driven metastatic dissemination. Normalizing the vasculature of tumors could hence sizably improve anti-cancer therapy. The binding of vascular endothelial cells (ECs) to the extracellular matrix (ECM) is mediated by integrins, a class of adhesive receptors that can assume active or inactive conformations, respectively characterized by high or low affinity binding to ECM ligands. Blood fluid shear stress is the main determinant of normal vascular architecture and function, its foremost outcomes being that of triggering integrin activation and fostering EC-to-ECM adhesion. As a direct consequence, ECs modify their adhesive interactions and reciprocal positions in space, finally giving rise to a remodeled, mature, and functional vascular tree. In this framework, inhibitors of integrin function should warrant a swift responsivity of EC-to-ECM adhesion to variations in blood flow-elicited forces. Therefore, pharmacological modulation of integrin function might be therapeutically exploited to ‘normalize’ the tumor vasculature.
We have previously shown how: (i) the chemorepulsive guidance cue semaphorin 3A (Sema3A) and its receptors plexins and neuropilin-1 (Nrp1) allow correct vascular morphogenesis by negatively modulating the conformational activation of integrins and inducing active/ECM bound integrin endocytosis; (ii) the abrogation of Sema3A-dependent integrin-inhibitory signals underpins the alterations that characterize tumor blood vessels; (iii) somatic gene transfer of Sema3A restores the physiological inhibition of endothelial integrins and effectively prevents cancer vascular abnormalities, thus improving the penetration of anti-neoplastic drugs and impairing metastases. In collaboration with the Laboratories of Transgenic Mouse Models and Cancer Cell Biology of our Institute, we generated a parenterally-deliverable mutant Sema3A* protein that, thanks to its ability to bind with high affinity the signaling receptor plexin A4, is much more active than its wild type counterpart both on cultured ECs and in mouse models of pancreatic cancer. More recently, we identified: i) a novel Sema that is endowed with an unpredictable in vivo pro-angiogenic activity ii) a novel signaling pathway that, by coordinating the endocytosis of active integrins and the exocytosis of freshly synthesized ECM, controls blood vessel formation and patterning both in vitro and in vivo.
Conclusions and perspectives:
Our data provide evidence of how the negative pharmacological modulation of endothelial integrins by Sema3A can be therapeutically exploited to improve the biodistribution of anti-neoplastic drugs and counteract the hypoxiadriven metastatic dissemination of cancer cells. It will therefore be crucial to further characterize the mechanisms and molecular determinants responsible for: (i) the inhibition of integrin-dependent EC adhesion by Sema3A; (ii) the selective Nrp1-dependent control of active integrin traffic in ECs.
Dora Tortarolo PhD Student
Fabiana Clapero, PhD Student
Giulia Villari, PhD
Donatella Valdembri, PhD
Giulia Mana, PhD
Noemi Gioelli, PhD