A new pharmaceutical target for schwannoma?

For schwannoma, a type of tumor that grows from Schwann cells, there are only surgical treatments. But now, work by the team of Anna Sablina (VIB-KU Leuven Center for Cancer Biology) reveals how a specific mutation contributes to tumor formation, which might lead to new therapeutic options. The work appeared in Cancer Communications.  

Schwann song 

The nerve cells in our peripheral nervous system are the cells that make us move, touch, and feel, among other things. Those nerve cells, though, do not work alone. In the intricate symphony of our nervous system, Schwann cells play a vital role. These unsung heroes wrap nerve fibers in a protective myelin sheath, ensuring smooth communication between our brain and the rest of the body. ​ 

Unfortunately, Schwann cells are not invincible. Enter schwannoma, a peculiar tumor that arises from Schwann cells. It’s like an unexpected twist in the nerve cell narrative. Schwannomas can sprout anywhere along our nerves, but they have a penchant for setting up camp in the head and neck regions. Schwannoma causes pain, numbness, weakness, hearing loss, and facial paralysis. Without available medicinal treatments, surgery is the only option. ​ 

A genetic disorder called schwannomatosis causes people to develop multiple schwannomas. Here’s the catch: surgery is currently the only remedy for these painful tumor growths.

LZTR1 and STAT1 

Anna Sablina, who leads the lab for mechanisms of cell transformation at the VIB-KU Leuven Center for Cancer Biology and her team have been dissecting the genetic underpinnings of schwannoma, focusing on one of the genes that is involved in this condition: LZTR1. Could that gene lead the way to new treatment options? ​ 

"We knew that LZTR1 was involved in cell growth and division," says Sablina, "but how exactly mutations in this gene contribute to schwannoma was much less clear." 

Using different imaging methods allowed researchers from the Sablina lab and their colleagues to compare schwannoma in mice with and without mutations in the LZTR1 gene. They found that mice with the LZTR1 mutation had more aggressive tumors than the mice without the mutation. 

"It was clear that the LZTR1 mutation played a significant role in the development of schwannoma," says Tonci Ivanisevic, PhD student at the Sablina lab, who led the study, "but what we really wanted to know is how, so we used proteomics to compare the levels of different proteins in human Schwann cells with or without LZTR1 mutation." 

And that comparison provided a crucial clue. The LZTR1 mutation activated the STAT1 pathway, which is involved in inflammation and immune response. The mutation induces a change – phosphorylation – in the STAT1 protein that leads to an increase in pro-inflammatory molecules called cytokines. ​ 

Finally, the researchers tested whether the STAT1 pathway could be a target for treating schwannoma, by using anti-STAT1 therapy. Indeed, STAT1 inhibition led to decreased tumor cell proliferation and metabolic activity, which provides a new route toward therapies for schwannoma patients, as drugs against STAT1 could be repurposed rapidly for such treatments. 

Publication 

Ivanisevic et al. Targeted STAT1 therapy for LZTR1-driven peripheral nerve sheath tumor. Cancer Communications, 2024. ​ 

Gunnar De Winter

Science Communications Expert, VIB

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gunnar.dewinter@vib.be