Mutant p53 drives integrin and EGFR recycling via RCP, leading to random movement and increased invasion as shown by stills of wound-scratch assays (A) and Matrigel invasion assays (B).

Image courtesy of Patricia Muller, Jim Norman and Karen Vousden, the Beatson Institute for Cancer Research, Glasgow, UK.

Wild-type p53 is a tumour suppressor protein that activates senescence and apoptotic cell death. Although almost all cancers contain a mutated p53 gene, the actual mechanism by which mutant p53 promotes cancer cell invasion is unknown. In Cell, Jim Norman, Karen Vousden and colleagues now report that mutant p53 drives invasion and random motility of cancer cells via increased α5β1 integrin signalling and loss of persistent migration and polarity.

In support of earlier studies, they demonstrated that expression of endogenous or exogenous mutant p53 in a variety of human cancer cells significantly induces cell migration and invasion through Matrigel. In vivo studies in mice also showed that mutant-p53-expressing cancer cells are more invasive and form more micrometastases than cells in which p53 was deleted. But how does mutant p53 enhance tumour cell invasion and metastasis?

To address this, the authors used time-lapse video microscopy and cell-tracking software and analysed the velocity and direction of cells moving into the wound in a scratch-wound assay. Interestingly, the cells expressing mutant p53 displayed a loss of directionality, although their speed of movement was not affected. Further imaging analyses revealed that mutant-p53-containing cells were unable to orientate their Golgi complex to face the wounded area and exhibited a disorganised actin cytoskeleton resulting in the collapse of the lamellipodia. This indicated that mutant p53 expression alters migration of cancer cells, favouring random motility and invasion.

Since the invasiveness of mutant-p53-expressing cancer cells depends on epidermal growth factor (EGF) and fibronectin as substrates, the authors next investigated the potential role of α5β1 integrin (a fibronectin-binding integrin) and EGF receptor (EGFR). Indeed, blocking integrins with specific antibodies inhibited the enhanced invasion and random motility of the cancer cells. Consistently, pharmacological inhibition of EGFR also repressed the effect on migration, which suggested that mutant-p53-mediated tumour invasion depends on integrin and EGFR signalling.

To further investigate how integrins affect mutant p53 function, they examined the rate of receptor internalisation following expression of mutant p53. Surprisingly, no change was detected in either integrin or EGFR internalisation; however, there was a pronounced increase in receptor recycling to the plasma membrane. Knock-down of Rab11 effector Rab-coupling protein (RCP) showed that p53-mediated integrin recycling was completely dependent on RCP. Furthermore, in RCP-deficient mutant-p53-expressing cells, migrational directionality was restored.

Taken together, this study demonstrates that mutant p53 expression enhances RCP-dependent integrin and EGFR recycling, which promotes random migration and invasion of cancer cells.

Author: Iley Ozerlat