Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, metastatic, nerve-associated tumors that occur sporadically (~50% of cases) or in association with the inherited syndrome neurofibromatosis type 1 (NF1), and a leading cause of death in neurofibromatosis patients. Despite current aggressive multimodal therapy, MPNST patients have a poor prognosis with high rates of tumor relapse and severe treatment-related side effects. There is currently no effective chemotherapeutic regimen for MPNSTs. This presents an urgent need to identify and develop alternative targeted therapies. Thus, identifying and targeting key regulatory pathways that are vital to MPNST formation are essential to overcoming this challenge. The objective of this application is to investigate the function of a novel signaling pathway, the Hippo pathway in peripheral nerve sheath tumorigenesis or MPNSTs that are not associated with NF1 mutations. The Hippo signaling pathway plays an important role in the control of cell growth, homeostasis, and tumorigenesis in various organ systems. Our preliminary studies show that loss of Lats1/2 kinases, Hippo signaling components, in the Schwann cell lineage leads to high grade GEM (Genetically Engineered Mouse)-PNST formation with full penetrance. Thus, our central hypothesis, based on our strong preliminary data, is that Lats1/2 functions as a novel tumor suppressor in MPNSTs, which has not been characterized previously in MPNSTs. We hypothesize that Lats1/2 and Lats- mediated downstream signaling events are essential for malignant peripheral nerve sheath tumorigenesis. This novel mouse model system for GEM-PNST initiation and growth will provide a unique opportunity to dissect the role of the Hippo signaling pathway in regulating MPNST formation. The proposed study will: 1) define the susceptible stages in the SC lineage for GEM-PNST initiation and progression due to Hippo signaling inactivation; 2) identify the critical pathways and signals that drive tumorigenesis in Lats1/2-deficient mice. 3) test the hypothesis that Hippo signaling effectors Yap and Taz are required for Lats1/2-mutant induced tumor formation. The long-term objective of our proposed studies is to develop therapeutic strategies for MPNST treatment by defining the function of Hippo signaling in the initiation and progression of MPNSTs and identifying the critical mediators of Lats1/2 in tumorigenesis. The long-term goal of the research proposed here is to identify therapeutic targets for the treatment of malignant peripheral nerve sheath tumors. Ultimately, these studies will establish a proof-of- principle for preclinical studies and develop effective therapies against tumor formation and progression in the patients with MPNSTs.
Malignant peripheral nerve sheath tumors (MPNSTs) are among the most devastating and intractable of the soft tissue sarcomas. They are highly aggressive, metastatic, nerve-associated tumors and a leading cause of death in neurofibromatosis patients. The proposed research will provide a better understanding of signaling and molecular control of peripheral nerve sheath tumor initiation and progression. It is relevant to the part of NIH's mission because the proposed studies will not only have scientific merits but also could offer new strategies in treating patients with peripheral nerve sheath tumors such as MPNSTs, neurofibromas, and schwannomas.
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