Tumor suppression by merlin: Mechanisms and therapeutic potentials
Hematology, Oncology
Final Report Abstract
Neurofibromatosis (NF) encompasses a group of genetic disorders characterized by the formation of tumors from Schwann cells, primarily categorized into three types: NF1, NF2, and schwannomatosis. This report focuses on NF2, which results from NF2 gene inactivation, leading to schwannoma formation. Our project aims to elucidate the mechanisms underlying NF2 pathogenesis and develop therapeutic strategies, leveraging our insights into merlin's regulatory roles in Ras-MAPK signaling pathways and Schwann cell interactions. We identified novel interactions between merlin and Ras, demonstrating that merlin's FERM domain interacts with Ras at the plasma membrane, crucial for regulating Ras-GAP activity. Loss of merlin leads to sustained Ras activation and downstream effects, implicating its role in contact inhibition of cell proliferation. Furthermore, our therapeutic strategy included the use of recombinant human Nrg1β (rhNRG1β) in preclinical NF2 mouse models, showing significant reductions in tumor growth and improved nerve regeneration. This pilot study motivated a larger, multicenter preclinical trial to validate these findings, focusing on biomarkers for treatment response. In parallel, we are developing a CRISPR-based gene editing therapy to directly address NF2 gene mutations, collaborating with the Children’s Medical Research Institute. This involves targeted delivery via AAV particles to Schwann cells, with promising preliminary results from our AAV library screening for optimal serotypes. Additionally, we are creating an orthotopic patient-derived xenograft (PDX) mouse model to better simulate schwannoma development in vivo, incorporating critical microenvironmental cues. This model aims to enhance our understanding of NF2 pathophysiology and facilitate the evaluation of new therapeutic interventions. Lastly, we are investigating lipid nanoparticles (LNP) as delivery vehicles for targeted therapy in NF2-related tumors, collaborating with Moderna. Initial studies aim to identify LNP candidates capable of reaching specific tumor cell types, with implications for broader therapeutic applications in NF-related conditions. Overall, this comprehensive research approach combines mechanistic studies, innovative therapeutic strategies, and model development to advance our understanding of NF2 and improve treatment outcomes for affected patients.
Publications
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Age-related changes in the peripheral nerves and the identification of exosomal biomarkers for neurofibromatosis type 2 and aging. PhD thesis.
Bischoff, Julia
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The NF2 tumor suppressor merlin interacts with Ras and RasGAP, which may modulate Ras signaling. Oncogene, 38(36), 6370-6381.
Cui, Yan; Groth, Susann; Troutman, Scott; Carlstedt, Annemarie; Sperka, Tobias; Riecken, Lars Björn; Kissil, Joseph L.; Jin, Hongchuan & Morrison, Helen
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Merlin cooperates with neurofibromin and Spred1 to suppress the Ras–Erk pathway. Human Molecular Genetics, 29(23), 3793-3806.
Cui, Yan; Ma, Lin; Schacke, Stephan; Yin, Jiani C.; Hsueh, Yi-Ping; Jin, Hongchuan & Morrison, Helen
