Cell adhesion and signalling in tumor progression and angiogenesis

Research project

The interactions of cells between each other and with the extracellular matrix are crucial for a variety of cellular functions such as adhesion, migration, proliferation and survival. The main molecular players involved in these interactions are cell adhesion molecules (CAMs), which include integrins, cadherins, immunoglobulin-like CAMs, and selectins. In the last decade, it has become increasingly clear that CAM function is far from being restricted to the structural support of cell-cell and cell-matrix adhesion. Rather, CAMs play an essential role in the regulation of various cellular functions, in some cases even independently on their adhesive properties.

Our group is interested in dissecting the novel, non-canonical function of immunoglobulin-like cell adhesion molecules (Ig-CAMs), both at the cellular and molecular levels and in clinically relevant contexts, most prominently cancer progression and tumor/microenvironment interactions.

We are currently pursuing two main lines of research:

1. The NCAM/FGFR interplay: molecular characterization and implications for cancer progression

Fig. 1: The NCAM/FGFR interplay [more info]

We have recently discovered a functional and physical interaction between neural-cell adhesion molecule (NCAM) and the fibroblast growth factor receptor (FGFR), a receptor tyrosine kinase (RTK) involved in intracellular signaling (Cavallaro et al., 2001) (Fig. 1). In the last few years, we have employed an integrated approach to investigate the biological relevance of the NCAM/FGFR interplay. The results pointed to NCAM as a novel, unconventional ligand for FGFR, which regulates the signaling activity, the intracellular trafficking and the cellular function of the receptor (Francavilla et al., 2007; Francavilla et al., submitted). Notably, NCAM-mediated regulation of FGFR activity is remarkably distinct from the effect of FGF, the classical FGFR ligand (Fig. 2). These studies, which established a new paradigm in the field of RTK function, paved the way for our current research. In particular, we wish to define the molecular mechanisms underlying the specific and peculiar impact of NCAM on FGFR function, and to obtain a global picture of the downstream biochemical and genetic pathways, using a systems biology approach.

Fig. 2: NCAM and FGF differentially affect the intracellular fate of FGFR and induce distinct FGFR-mediated cellular responses. [more info]

Together with the notion that both NCAM expression and FGR signaling are aberrant in various cancer types (Zecchini & Cavallaro, in press), our observations provided the rationale for exploring the possible role of the NCAM/FGFR interaction during tumor development (Zecchini et al., submitted). We are pursuing this objective by investigating the effect of the NCAM/FGFR complex not only in the malignant behavior of tumor cells, but also in the interaction between cancer and its microenvironment.

2. Novel function of L1 in the immune and vascular systems: implications for tumor/microenvironment interactions

L1 is a cell adhesion molecule abundantly expressed in the nervous system, where it plays a pivotal role in various steps of brain development. L1 is also expressed in non-neural cell types such as a subset of leukocytes, where, however, its role remains elusive. By generating a conditional knockout mouse model, we have recently defined a novel, crucial role of L1 in the trafficking of dendritic cells across the vessel wall, a key step in the immune response. Furthermore, we have provided evidence for the induction of L1 expression in the endothelium of pathological vessels (i.e., associated to cancer or inflammation) (Fig. 3), an event that supports the transendothelial migration of immune cells (Maddaluno et al., 2009). We now aim at gaining insights into both the molecular mechanisms underlying the L1-dependent crosstalk between inflammatory and endothelial cells and the global role of L1 in the immune and vascular systems.

Fig. 3: Endothelial expression of L1 in pathological vessels [more info]

L1 is also aberrantly expressed in certain tumor types, such as ovarian carcinoma where L1 levels correlate with poor prognosis and the molecule promotes cancer cell malignancy (Zecchini et al., 2008). Taken together, these observations point to L1 as a central player in the interaction of tumor cells with the surrounding microenvironment, possibly mediating cancer-associated angiogenesis and inflammation, as well as metastatic dissemination (a process that shares striking similarities with immune cell trafficking). These hypotheses are currently being verified by taking advantage of appropriate in vitro and animal models, focusing on ovarian carcinoma as well as on other clinically relevant tumor types.