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Implantation and Monitoring by PET/CT of an Orthotopic Model of Human Pleural Mesothelioma in Athymic Mice
Published on: December 21, 2019
Gene therapy for diffuse pleural mesotheliomas in preclinical models by concurrent expression of NF2 and SuperHippo
Rui Zhu1, Xincheng Liu1, Xu Zhang1
1Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Abstract:
Diffuse pleural mesothelioma (DPM) is a lethal cancer with a poor prognosis and limited treatment options. The Hippo signaling pathway genes, such as NF2 and LATS1/2, are frequently mutated in DPM, indicating a tumor suppressor role in the development of DPM. Here, we show that in DPM cell lines lacking NF2 and in mice with a conditional Nf2 knockout, downregulation of WWC proteins, another family of Hippo pathway regulators, accelerates DPM progression. Conversely, the expression of SuperHippo, a WWC-derived minigene, effectively enhances Hippo signaling and suppresses DPM development. Moreover, the adeno-associated virus serotype 6 (AAV6) has been engineered to deliver both NF2 and SuperHippo genes into mesothelial cells, which substantially impedes tumor growth in xenograft and genetic DPM models and prolongs the median survival of mice. These findings serve as a proof of concept for the potential use of gene therapy targeting the Hippo pathway to treat DPM.
Insights
Gene therapy using AAV6 to deliver NF2 and SuperHippo genes shows promise for treating diffuse pleural mesothelioma (DPM). This approach enhances Hippo signaling, inhibits tumor growth, and extends survival in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Diffuse pleural mesothelioma (DPM) is an aggressive cancer with limited therapeutic options.
- Mutations in Hippo signaling pathway genes (e.g., NF2) are common in DPM, suggesting their tumor suppressor function.
- Downregulation of WWC proteins, Hippo pathway regulators, accelerates DPM progression.
Purpose of the Study:
- To investigate the therapeutic potential of restoring Hippo signaling in DPM.
- To evaluate the efficacy of gene therapy using AAV6 to deliver NF2 and SuperHippo in DPM models.
Main Methods:
- Utilized DPM cell lines and genetically engineered mouse models with Nf2 knockout.
- Engineered adeno-associated virus serotype 6 (AAV6) for gene delivery.
- Assessed tumor growth and survival in xenograft and genetic DPM models.
Main Results:
- Downregulation of WWC proteins accelerated DPM progression in NF2-deficient models.
- Expression of SuperHippo, a WWC-derived minigene, enhanced Hippo signaling and suppressed DPM development.
- AAV6-mediated delivery of NF2 and SuperHippo significantly impeded tumor growth and prolonged survival in DPM models.
Conclusions:
- Restoring Hippo pathway function via gene therapy is a viable strategy for DPM treatment.
- AAV6-based gene therapy targeting NF2 and SuperHippo demonstrates significant preclinical efficacy against DPM.
- These findings provide a proof of concept for novel gene therapies for diffuse pleural mesothelioma.
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