The discovery of neurofibromatosis type II identifies a potential new way to fight cancer

Neurofibromatosis type II (NF2) is a rare genetic disorder affecting approximately one in four people. About half of these people are genetically ill, while the other half develop spontaneous mutations without a family history.

This disease produces tumors along the nerve fibers, including the auditory nerves. But tumors are "benign" because they don't spread to other organs. Most patients with NF2 develop in childhood or adolescence, and their condition progresses rapidly. The bilateral hearing is eventually lost. If they are not treated, most patients die before the age of 20.

The NF2 gene produces the Moesin-Ezrin-Radixin-Like Protein, referred to as the Merlin protein, which links the proteins produced by NF2 to a larger family of proteins. When the "Merlin" protein is not working, people will develop a slow-growing, life-threatening auditory nerve tumor, NF2, which destroys their hearing and balance.

A study published in Science Signaling reported that scientists at the Children's Hospital of Cincinnati have discovered more about how Merlin works behind the scenes through a grid of more than 50 other proteins. For people suffering from NF2, this finding has driven the tracking of drug therapies for diseases that have so far required surgery.

These findings also promote a concept that has a broader impact on cancer research-the tumor's response to physical and other mechanical signals is impaired. This opens up new possibilities for the development of new cancer therapies.

The lab team used a technique called proximity biotinylation, which was developed more than a decade ago and has become a tool for identifying protein-protein interactions. This new technology not only reveals proteins that interact with Merlin but also discovers that Merlin operates at the edge, which is called a cell-linked complex.

The study mapped a grid of more than 50 other proteins in close proximity to Merlin, which greatly advanced the pace of combating neurofibromatosis.

Robert Hennigan, the first author of the paper, believes that every protein in these grid relationships needs further exploration and development of drugs. Currently, a protein called ASPP2 has emerged as a potential target.

When working properly, the data suggests that Merlin helps cells understand their physical environment, including other cells belonging to their neighbors. When cells are too crowded, Merlin may shut down excess structure through ASPP2 and other proteins found. However, when Merlin fails, the tumor can settle, grow and begin to push the surrounding cells to make room.

Previously, researchers suspected that Merlin's growth-suppressing function might act by inhibiting the signal produced by external growth factors, but the study showed that Merlin responded to physical cues, such as mechanical forces.

Evidence for mechanical signaling as a target for cancer control. The study reports that ASPP2 is a widely regulated regulator of the cancer suppressor protein p53 and is directly related to Merlin.

Based on new information about how Merlin works, ASPP2 connectivity suggests that targeting other mechanical signaling pathways may be an important way to prevent tumor growth when other treatments fail.

The technology, called Proximity Biotinylation, was first introduced to the Cincinnati Children's Hospital and is one of the few findings worldwide based on this approach. This approach represents a new way of thinking about NF2, and in the long run, there are many potential applications for this approach.

Now, scientists can see all the proteins in the protein grid. The next major step in the fight against NF2 will be to determine how the protein works as a network and then find ways to influence the network.