Strategies based on blocking the fibronectin synergy site for the treatment of solid malignant tumors

The extracellular matrices (ECM) are molecular networks that serve not only as the scaffold upon which cells are organized to form tissues but also provide essential biochemical and biomechanical cues that direct cell behavior. The malignant transformation of cancer cells is determined by both cell intrinsic properties, such as mutations, and extrinsic variables, such as the mixture of other cells in the tumor microenvironment and the ECM that they assemble. ECMs surrounding malignant solid tumors are fibrotic with abnormally increased stiffness. This feature was considered a mere consequence of the highly proliferative activity of the tumor, but abundant experimental evidence has changed the paradigm and now is well accepted that the high tumor rigidity potentiates de-differentiation, proliferation and invasion of tumor cells. Cancer-associated fibroblasts (CAFs) and infiltrating hematopoietic cells are major inducers of cancer stiffening. FN is a cell-adhesive protein and one of the firsts and more abundantly present in the stroma of primary tumors and metastatic foci. FN forms fibrillar and elastic networks that nucleate collagens and proteoglycans. Cells sense mechanical signals from their microenvironment through integrin receptors. FN contains two motifs, the RGD site and the synergy site, present in two adjacent modules (FNIII10 and FNIII9, respectively) that work in tandem to specifically regulate integrin-mediated cell adhesion, FN fibrils assembly and mechanosignaling. Upon a5b1 integrin binding to the RGD region and the nearby FN-synergy site, adhesions form and assemble large molecular signaling hubs that transduce information on ECM rigidity into the cell interior. Our project aims to explore a novel approach to prevent/reduce tumor growth by diminishing tumor cell mechanosensing alone or in combination with strategies impairing cell adhesion. The FN-synergy site is not critical for mesenchymal cell adhesion when tissue stiffness and av-class integrin expression are not perturbed. However, the synergy site becomes crucial to maintain cell adhesion when tensional forces increase above the physiological threshold, or when av-class integrin expression is lacking. Based on these findings, we are testing the hypothesis whether impairing the a5b1 adhesion reinforcement by blocking the synergy site in breast cancer prone mice represents a powerful strategy to curb tumor growth and metastasis, and whether concomitant application of Cilengitide, an av-class integrin inhibitor, increase its beneficial effect on tumorigenesis. To obtain a comprehensive picture of how FN-mediated mechano-sensing interferes with cancer, we will investigate an a5-synergy site blocking peptide-mimetic for in vivo use.

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