Background
The existence of multicellular organisms relies upon cell-to-cell and -extracellular matrix (ECM) adhesion, so does cancer growth and invasion. In particular, vertebrates built on a new set of ECM proteins and their cognate integrin receptors for normal vascular development. Notably, adhesive and structural abnormalities of tumor vessels impair anti-cancer drug delivery. Moreover, alterations in integrin adhesive properties allow cancer cells to violate the laws of normal tissue architecture and to invade.
Achievements
Integrins exist in different activation states in terms of affinity for ECM proteins. We firstly observed that while angiogenic growth factors, such as vascular endothelial growth factor-A (VEGF-A), promote integrin activation in vascular endothelial cells (ECs), soluble semaphorins, e.g. SEMA3A, inhibit integrin function via the neuropilin (Nrp)-plexin receptor complex that switches off the small GTPase R-Ras, a well-known integrin activator. Moreover, during development ECs self-produce their own SEMA3 that inhibit integrins and hence endow the vascular system with the flexibility required for its reshaping. Fittingly, we found that ECs of abnormal cancer vessels do not longer self-produce SEMA3 and display over-active integrins. Recently, we discovered that, independently from its role as VEGF-A and SEMA3A co-receptor, Nrp1, which is expressed both in ECs and cancer cells, preferentially stimulates the traffic and function of fibronectin-binding integrins such as α5β1, an integrin involved both in angiogenesis and tumor invasion.
Goals
(i) Identification of R-Ras effectors responsible for integrin activation; (ii) characterization of the molecular mechanisms by which Nrp1 and its ligands regulate integrin function; (iii) design and validation of SEMA3A-like super-agonists that inhibit integrins of tumor ECs.
Internal collaborations
Laboratory of Transgenic Mouse Models: validation of SEMA3A-like super-agonists in transgenic mouse models of multistep carcinogenesis; Laboratory of Membrane Trafficking: role of endocytic proteins in integrin trafficking.
