| Studies in mice and cells have shown convincingly that expression of mutant p53 is not equivalent to loss of p53 and strongly support a gain-of-function for mutant p53 in promoting invasion. We therefore aim to elucidate the mechanisms by which mutant p53 enhances the metastasis observed in vivo and potentially identify novel therapies to specifically prevent mutant p53 invasion. Human cell lines lacking WT p53 and stably expressing mutant p53 can promote their ability to invade in an in vitro matrigel assay, compared to vector control cells. In wound healing assays, these mutant p53 cells show a pronounced loss of directionality in comparison to vector control cells that move persistent into a wounded area. Loss of directionality and increased invasion have previously been associated with increased integrin-dependent signalling. In other cancer types, clinical trials are currently conducted to prevent signalling through these integrins and thereby prevent invasiveness. Interestingly, our preliminary results in mutant p53 cells, reveal a marked induction of this integrin signalling pathway and inhibition of integrins can clearly prevent the loss of directionality and increased invasion. These findings therefore open the possibility to specifically identify therapeutics to inhibit mutant p53 invasiveness by blocking integrin dependent signalling. |
