Innovative Holland Lab mouse model helps tease apart YAP1’s role in brain cancer

From the Holland Lab, Cancer Basic Biology Program, Cancer Consortium.

Despite being relatively common, meningiomas – a type of brain tumor that accounts for just over 36% of brain cancer diagnoses – aren’t well-known to most people. That could be because they tend to be relatively benign, slow growing with few initial symptoms; however, meningiomas can be debilitating when malignant and recur even after multiple surgeries, ultimately leading to death. “There have never been adequate mouse models for meningioma, in spite of this tumor being the most common brain tumor in humans,” said Dr. Eric Holland, the leader of the Fred Hutch Human Biology Division and a researcher with abundant experience studying different forms of brain cancer. “Because these tumors do not grow well in culture, mechanistic work in meningiomas has been limited.” That means that the cause of meningiomas, and what leads them to be benign or malignant, has been a mystery for quite some time. A recent publication led by Dr. Frank Szulzewsky, a senior staff scientist in the Holland Lab, broke this barrier by developing a reliable model for meningiomas and casting light on their mechanistic cause.

Around half of meningiomas exhibit functional loss of the tumor suppressor gene NF2, a component of the Hippo cellular signaling pathway that regulates cell growth by dampening the activity of transcriptional coactivator proteins such as YAP1. The Holland Lab has previously investigated the role of YAP1 gene fusions, but this work was in other cancer types. “These other cancers that we had previously worked on are very rare and most of them are driven by recurrent gene fusions, including YAP1 gene fusions” explained Dr. Szulzewsky. “Meningiomas in turn are very common and are usually not driven by gene fusions, but by other somatic mutations, such as inactivation of the NF2 gene. In a sense, this work was a continuation of our previous paper – at least in the beginning, when we started working on YAP1-MAML2, a gene fusion that was discovered in a rare subset of pediatric NF2-wild type meningiomas.” First, Dr. Szulzewsky and colleagues used RNA-sequencing to show that the gene expression profiles of YAP1 fusion-positive meningiomas resemble the more typical NF2 mutant meningiomas. He then forced expression of the YAP1-MAML2 fusion in mice and found that it induced the formation of meningioma-like tumors. This was a huge breakthrough for the team. “The most exciting moment was when Frank first got what seemed like a meningioma in a mouse caused by a YAP fusion that is found in human meningioma,” said Dr. Holland. “And then when he was able to generate the same type of tumor by expressing constitutively active YAP, clarifying the mechanism.” Dr. Szulzewsky chimed in, “we quickly realized that this fusion is just an exception that confirms the general rule for (a large subset of) meningiomas: a large percentage of these tumors are driven by de-regulated YAP activity, which can be achieved in several different ways – loss of inhibitors of YAP (NF2) or by generating a fusion that is insensitive to the inhibitive effect of NF2/LATS (aka the Hippo pathway). Overall, de-regulated YAP activity seems to be the oncogenic driving force in these tumors.”

An abstract graphic with brightly colored, amorphous shapes overlapping. At the intersection of the shapes are sections of brain tissues and a schematic of a pathway showing the relationship between YAP overexpression and development of meningiomas.
Dr. Frank Szulzewsky, of the Holland Lab in the Human Biology Division, recently showed that de-regulated activity of the transcriptional coregulator YAP is a major driver of meningiomas. Figure provided by Dr. Szulzewsky; Image generated by Hannah Mathy at Rosanna, Inc.

As for what’s next for the Holland Lab? “We are creating a very large database of RNA seq of human meningiomas derived from multiple institutions,” said Dr. Holland. “That dataset is being compiled into one very large, dimension reduced landscape which will help us better identify the biology of the tumors that are likely to recur after successful surgery, and for which we need better therapies.” Dr. Szulzewsky sees this work as particularly important for the malignant meningiomas: “The benign tumors which are slow growing and can be easily surgically removed usually just exhibit NF2 loss, but the more aggressive tumors that actually recur repeatedly and kill people have additional mutations and drivers. So we would like to use our models to study how additional potential oncogenic drivers influence disease behavior and clinical outcome.”

The Holland Lab sits on the third floor of the Hutchinson building, right next to my lab, and we’re a collaborative bunch. Drs. Taran Gujral and Patrick Paddison also contributed to this study, and will continue to contribute in the future. Dr. Szulzewsky adds, “We are now using these models to test the efficacy of YAP1-TEAD inhibition as well as other potential downstream inhibitors in a collaboration with Taran.” These findings were exciting and surprising for multiple reasons and fed into another intriguing observation; “it is beginning to look like the really bad meningiomas have significant similarity to muscle development,” mused Dr. Holland. “But it is too early to say anything about that. We are talking with Dr. Stephen Tapscott about how we should be thinking about this. It will be another HB collaboration coming up…”

This work was funded by the National Institutes of Health, the Ivy Foundation, the Climb to Fight Cancer Fellowship, and the Preclinical Imaging Shared Resource of the Cancer Consortium.

Cancer Consortium members Dr. Eric Holland, Dr. Patrick Paddison, and Dr. Taran Gujral contributed to this work.

F Szulzewsky, S Arora, AKS Arakaki, P Sievers, DA Almiron Bonnin, PJ Paddison, F Sahn, PJ Cimino, TS Gujral and EC Holland. 2022. Both YAP1-MAML2 and constitutively active YAP1 drive the formation of tumors that resemble NF2 mutant meningiomas in mice. Genes & Development. 36:1-14.