Pleural mesothelioma is a rare and highly malignant tumor that originates from mesothelial cells on the surface of the pleura and is often closely related to asbestos exposure. Although immunotherapy such as immune checkpoint inhibitors can improve the survival of patients to a certain extent, the overall efficacy is limited. The median overall survival of patients is only about 18 months, and the prognosis is not ideal. Therefore, it is urgent to further explore and develop new strategies for the treatment of pleural mesothelioma.
Studies in recent years have shown that the pathogenesis of pleural mesothelioma involves inactivation mutations of multiple tumor suppressor genes. The results of whole exome sequencing of samples from patients with pleural mesothelioma showed that multiple tumor suppressor genes such as NF2, BAP1, CDKN2A/B and TP53 are often mutated or deleted in patients. In addition, LATS2 inactivation mutations are also common in mesothelioma patients. NF2 and LATS2 are important adaptor proteins and kinases in the Hippo tumor suppressor signaling pathway, respectively. The high-frequency mutations of these genes indicate that the Hippo signaling pathway plays an important role in the occurrence and development of pleural mesothelioma, suggesting that the Hippo signaling pathway has the potential to become a therapeutic target for pleural mesothelioma.
In October 2024, researchers from the Institute of Biomedical Sciences, Fudan University, China, published a research paper titled "Gene therapy for diffuse pleural mesotheliomas in preclinical models by concurrent expression of NF2 and SuperHippo" in Cell Reports Medicines. The study reported a new gene therapy strategy for pleural mesothelioma based on adeno-associated virus (AAV), and verified the effectiveness of the strategy through a genetic tumor model of mouse pleural mesothelioma.
Figure 1. AAV6 expressing both NF2 and SuperHippo is a potential gene therapy for DPM. (Zhu R, et al., 2024)
The Hippo signaling pathway is usually regarded as a "linear" kinase cascade reaction, that is, MST1/2 kinases and MAP4Ks kinases regulate YAP/TAZ transcriptional coactivators by acting on LATS1/2 kinases. In order to deeply understand how LATS1/2 and YAP/TAZ integrate upstream signals, the researchers systematically sorted out the core molecular network of the signaling pathway and proposed two dual-signal module architectures, HPO1 and HPO2, in which WWC and NF2 mediate the activation of the two signal modules respectively, and developed the SuperHippo mini-gene molecular tool based on the mechanism of action of WWC protein.
The frequency of inactivating mutations of NF2 in pleural mesothelioma is as high as 40%, suggesting that HPO2 signaling has a potential regulatory role in this disease, which has been verified in previous studies. This study explored the function of HPO1 signaling (WWC and SAV1) in mesothelioma using mesothelioma cell lines and mouse genetic models. The results showed that when the HPO1 signal was lost, the proliferation in vitro and the tumorigenic ability of mesothelioma cells in vivo were significantly enhanced. When both HPO1 and HPO2 signals are missing, the mouse pleural mesothelium is significantly thickened and presents the characteristics of pleural mesothelioma. Therefore, HPO1 signal is also involved in the disease process of pleural mesothelioma, and activation of HPO1 signal should have anti-cancer potential. Indeed, overexpression of SuperHippo in a mouse pleural mesothelioma genetic model can significantly inhibit tumor progression.
Based on these findings, the research team proposed a new strategy for the treatment of mesothelioma: on the one hand, the normal function of HPO2 is restored by replenishing NF2, and on the other hand, HPO1 is superactivated by overexpressing SuperHippo, while the activity of HPO1 and HPO2 is increased, maximizing the activation of the Hippo signaling pathway, thereby giving full play to its anti-cancer function. Because the NF2 and SuperHippo genes are small, they can be carried and expressed by the same AAV viral vector, achieving dual effects. The study also showed that AAV6 can effectively infect mesothelial cells, and the team finally prepared AAV6-SuperHippo-NF2 virus for preclinical research. In the Nf2/Trp53 mouse pleural mesothelioma model, the virus significantly inhibited tumor progression and prolonged mouse survival, showing significant anti-cancer potential.
| Cat.No. | Product Name | Price |
|---|---|---|
| VLP-AAV004 | AAV6 Virus-Like Particles (Empty Capsids) | Inquiry |
| AAV00207Z | AAV6-Syn-iCre | Inquiry |
| AAV00209Z | AAV6-CAG-FLPo | Inquiry |
| AAV00198Z | scAAV6-GFP | Inquiry |
| AAV00199Z | scAAV6-Cre | Inquiry |
| AAV00204Z | AAV6-CAG-iCre | Inquiry |
| AAV00208Z | AAV6-Syn-FLPo | Inquiry |
| AAV00402Z | scAAV6-CAG-GFP | Inquiry |
| AAV00515Z | AAV6-CAG-FLuc | Inquiry |
| AAV00518Z | AAV6-hSyn-FLuc | Inquiry |
| AAV00205Z | AAV6-CAG-Cre-GFP | Inquiry |
| AAV00212Z | AAV6-EF1α-GFP | Inquiry |
| AAV00517Z | AAV6-CAG-Cre-2A-GFP | Inquiry |
| AAV00210Z | AAV6-CMV-FLPo | Inquiry |
| AAV00211Z | AAV6-MHCK7-GFP | Inquiry |
In summary, this study verified the tumor suppressor effect of the Hippo signaling pathway, especially the HPO1 signaling module, in pleural mesothelioma through pleural mesothelioma cell lines and mouse models. In addition, the study also proposed a new gene therapy program and verified its feasibility in a mouse genetic model. These findings provide conceptual verification for the treatment of pleural mesothelioma by targeting the Hippo signaling pathway through gene therapy and lay the foundation for subsequent clinical translational research.
Reference
Zhu R, et al. Gene therapy for diffuse pleural mesotheliomas in preclinical models by concurrent expression of NF2 and SuperHippo. Cell Reports Medicine, 2024, 5(10).