Abnormal activation of a key protein called YAP may be related to the occurrence of certain brain tumors, which brings new ideas to the treatment of patients who lack specific gene mutations.
Discovery of YAP1-MAML2 fusion gene
Among meningioma patients in children and adolescents, some individuals do not have a mutation in the NF2 gene and are classified as "wild type". Research carried out in recent years has found that there is a special genetic mutation within these tumors, that is, the fusion of the YAP1 gene and the MAML2 gene. This fusion event causes changes in the cell's normal regulatory mechanisms. YAP1 protein is generally strictly controlled, but the addition of MAML2 is like a key, continuously activating the growth-promoting function of YAP1, which may then drive the formation of tumors.
Similarity to NF2 mutated tumors
Despite the differences in genetic origin, the molecular characteristics of meningiomas carrying the YAP1-MAML2 fusion gene are very similar to those of classic NF2-mutant meningiomas. The researchers analyzed RNA sequencing data from human tumor samples and found that the two types of tumors were very similar in their overall gene expression profiles. More importantly, they all show the common characteristic of abnormal activation of the YAP signaling pathway. This shows that although the starting points are different, they eventually lead to the "engine" of YAP going out of control.
The YAP signaling pathway is abnormally activated
In YAP1 fusion-positive meningiomas, NF2 protein function is intact, but YAP signaling remains on. The specific situation is that the expression levels of a series of downstream target genes regulated by YAP, such as CTGF and CYR61, are significantly increased. These genes are generally involved in cell proliferation and survival processes. Data show that in some YAP1 fusion-positive tumor samples, the expression of these target genes is even higher than that of some tumors with NF2 mutations, which shows that the activity of the YAP pathway is very strong.
Mouse model confirms carcinogenic potential
In order to directly verify the carcinogenicity of the YAP1-MAML2 fusion gene, scientists conducted relevant experiments in mouse models. They introduced the human YAP1-MAML2 fusion gene into the meningeal cells of mice with the help of viral vectors. The results showed that forced expression of this fusion gene was sufficient to induce intracranial tumors in mice. The morphological characteristics of these mouse tumors under the microscope are very similar to human YAP1 fusion-positive or NF2 mutant meningiomas, providing direct evidence for the driving role of the fusion gene.
Interaction with TEAD is key
YAP1 protein plays a cancer-promoting role, which mainly relies on binding with TEAD family transcription factors in the nucleus. Studies have shown that the YAP1-MAML2 fusion protein must also bind to TEAD to cause cancer. In animal experiments, if the binding ability of the fusion protein to TEAD is artificially destroyed, its ability to induce tumors will be lost. This discovery reveals the molecular core of the fusion gene's action and also suggests that interfering with YAP-TEAD binding may be a potential therapeutic strategy.
Constitutively active YAP1 is sufficient to induce tumors
Further more convincing evidence comes from another experiment, in which researchers expressed a modified YAP1 protein that is always active in mouse meningeal cells, namely YAP1 S127/397A. Subsequent corresponding results showed that just this activated YAP1 protein itself was sufficient to drive the final formation of meningioma-like tumors in mice. This experiment clearly demonstrates that overactivation of YAP1 is a key driver of tumor formation, and that the MAML2 moiety presumably plays a major role in "locking" YAP1 in an activated state.
For many patients with NF2 wild-type meningiomas who lack effective targets, is it possible that drug development based on the YAP-TEAD interaction will become the most promising treatment direction in the future? Feel free to share your personal views in the comment area.
