Metastasis is the main cause of cancer related death, largely dependent on the formation of new blood vessels (angiogenesis), that sustains the growth and the invasiveness of cancer cells. Existing therapies targeting either tumor-associated angiogenesis or metastatic dissemination are limited and poorly effective. Here we exploit an innovative strategy, named FunSel, for the in vivo functional selection of secreted factors able to contrast cancer cell invasiveness. The top ten identified factors were first tested in vitro for their capacity to block cell migration, and the most potent ones were further validated in vivo for their capacity to inhibit cancer growth. The AAV-mediated overexpression of a top hit, EMI Domain Containing 2 (EMID2), induced a 30% reduction of the tumor volume, paralleled by a marked inhibition of tumor angiogenesis. We showed that EMID2 modified the tumor microenvironment by inhibiting the activation of cancer-associated fibroblasts and altering the composition and mechanical properties of the extracellular matrix. Finally, its expression in lungs was able to prevent the formation of metastasis.
The same strategy allowed us to identify factors promoting the invasion of cancer cells. Among them, we identified BD33 as a novel factor that promotes cancer cell growth, migration and angiogenesis both in vitro and in vivo.
In conclusion, the FunSel approach led to the identification of a novel series of secreted factors as the most potent ones to modulate the growth and invasiveness of cancer cells in vivo, paving the way for the development of innovative therapeutic opportunities to control tumor progression and modulate angiogenesis.
