Shedding light on metastasis in the brain

Micrographs of cells in the process of adapting their shape to traverse microtunnels with a diameter 10 times smaller than the cell size.

Metastasis in the brain is common in breast cancer and one of the most common causes of death. To reach the brain, breast cancer cells must migrate from the tumor where they originated. They have to modify their shape and be able to move forward through the small spaces available. They also have to release some proteins that, like a drill, break down the barriers that appear during their journey. And finally, in the case of breast cancer cells that metastasize in the brain, they need proteins – serpins – that overturn the natural defenses of the brain, allowing the growth of the tumor in its new location.

Now, researchers have identified that a low level of the ion channel Piezo2 – a type of protein that forms pores through which ions enter and exit cells – makes the secretion, invasion and proliferation of serpins difficult, while a high level favors them.

“Our initial goal was to find out what triggers the breast cancer cells in the brain to release the serpins, because these break down the brain’s defenses,” explains Carlos Pardo-Pastor, first author of the paper. “During a metastatic cell’s journey, it has to adapt to many changes in the physical and mechanical properties of its environment, so we hypothesized that ionic channels that detect mechanical and osmotic changes in cells could be relevant in metastasis.”

Breast cancer cells that specifically metastasize in the brain present higher levels of the Piezo2 channel – a selective port which allows calcium flow when the cell detects changes in the rigidity of the environment, or when it crosses excessively narrow spaces. This calcium signal, in turn, triggers a wide range of responses including the secretion of serpins and the generation of structures known as invadosomes, which are necessary to perforate the extracellular matrix and allow the cells through.

The discovery could turn these channels into the target of new drugs that decrease the risk of metastasis.

Reference article: C. Pardo-Pastor, F. Rubio-Moscardo, M. Vogel-González, S. A. Serra, A. Afthinos, S. Mrkonjic, O. Destaing, J. F. Abenza, J. M. Fernández-Fernández, X. Trepat, C. Albigés-Rizo, K. Konstantopoulos and M. A. Valverde. (2018). Piezo2 channel regulates RhoA and Actin cytoskeleton to promote cell cell mechanobiological responses. Proceedings of the National Academy of Sciences, epub ahead of print