Like any specialized field, cancer biology has its fair share of technical vocabulary and jargon; two examples which you may be familiar with are the terms tumor suppressor (a gene whose loss or inactivation promotes the development of cancer) and oncogene (a gene encoding a protein whose activity promotes the development of cancer). While definitions like this help promote communication and shared understanding of important concepts, it’s important to realize that there are almost always exceptions to the rules—the reality of a complex disease like cancer is often less straightforward than our textbook definitions would have us believe. Today’s story, coming to us from the Holland Lab in the Human Biology Division at Fred Hutch, nicely illustrates this point for one type of brain cancer.
Our stage is meningioma, a cancer that originates in the membranes lining the brain and spinal cord. While meningiomas are the most common type of primary brain cancer in adults, the majority of cases are benign. In fact, they are sometimes so unobtrusive that they’re only discovered on autopsy for a patient who died of a different cause! When they are aggressive, however, meningiomas mean business, growing quickly, rebounding after surgical resection, and precociously gaining resistance to standard treatments. About half of all meningiomas are characterized by functional loss of a tumor suppressor called NF2, a core regulator of several cellular signaling pathways, including the transcription factor (and oncogene) YAP1. In general, here’s how it works: NF2 normally phosphorylates and inactivates YAP1; a meningioma which loses NF2 function will therefore over-activate YAP1, which recruits a binding partner called TEAD; YAP1-TEAD then promote the expression of various pro-growth pathways which ultimately drive tumorigenesis. “That’s how we generally thought of it,” noted Dr. Frank Szulzewsky, a staff scientist in the Holland Lab who led the recent study, “until we started stratifying the data into benign-versus-aggressive subcategories and noticed something very interesting.”
Indeed, when the team queried an RNA-sequencing dataset from nearly 1,300 human meningioma samples and divided NF2-mutant meningiomas into ‘benign’ and ‘aggressive’ subcategories, they noticed that several canonical YAP1 targets were significantly under-expressed in samples from aggressive tumors compared to benign ones. To confirm that this effect was due to the tumor cells themselves (and not infiltrating immune cells, for instance), the team also queried an independent meningioma single-cell RNA sequencing dataset, where they found an identical trend: on average, tumor cells from aggressive meningiomas showed lower expression of YAP1 targets than cells from benign tumors. Turning back to the larger dataset and looping in available metadata about these patients, the team found another startling trend: lower expression of YAP1 target genes (i.e. lower YAP1 activity) was significantly associated with a shorter time to recurrence (i.e. a more aggressive cancer). As Dr. Szulzewsky continued, “Even though NF2-mutant meningiomas on the whole demonstrated higher YAP1 activity than NF2-wild type meningiomas (consistent with what we know about the NF2-YAP1 relationship noted above), having the ability to look deeper into the data revealed that this effect was driven primarily by the benign cases—aggressive tumors actually showed decreased YAP1 activity on par with that of NF2-wild type tumors.”
How might aggressive meningiomas accomplish this YAP1 downregulation? To figure this out, the team focused their attention on known YAP1 regulators and probed their expression in the aforementioned single-cell RNA sequencing dataset. Surprisingly, this analysis revealed two YAP1 suppressors that were highly expressed in cells from aggressive tumors: VGLL4, a transcription cofactor which antagonizes YAP1 by competing for its TEAD binding partner, and FAT3/4, two related membrane proteins which have been shown to functionally substitute for NF2 in certain situations. Finally, the team overexpressed VGLL4 in a benign NF2-mutant meningioma cell line and found that this was indeed sufficient to reduce the activity of a YAP1 reporter and decrease the expression of several YAP1 target genes, just as they had observed in the tumor datasets.
What might all this mean? “On a high level, these data suggest that it’s not always as simple as ‘losing a tumor suppressor leads to oncogene activation, which drives tumorigenesis’,” noted Abigail Parrish, first author of the study. Dr. Szulzewsky added, “To be sure, while these data suggest that aggressive meningiomas intentionally downregulate YAP1, they don’t prove that low YAP1 activity is actually beneficial for these tumors, which we are in the process of determining. What they do argue, however, is that aggressive meningiomas are fundamentally different than benign meningiomas in ways that may be relevant to their treatment—you could imagine, perhaps, that our findings here might influence the extent to which benign versus aggressive meningiomas respond to a new generation of YAP1-TEAD inhibitors which are currently in development for several tumor types.”
The spotlighted work was funded by the National Institutes of Health and supported by the Genomics and Bioinformatics Shared Resource at Fred Hutch.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium member Dr. Eric C. Holland contributed to this study.
Parrish, A. G., Arora, S., Thirimanne, H. N., Rudoy, D., Schmid, S., Sievers, P., Sahm, F., Holland, E. C., & Szulzewsky, F. (2024). Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4. https://doi.org/10.1101/2024.05.30.596719