Inactivating germ line mutations in the neurofibromatosis type 1 (NF1) gene are responsible for the many manifestations of this disease that range from intellectual deficits, to autism, to bone abnormalities and to many forms of pediatric cancer. For 20 years we have used gene knockout technology to model a diversity of aspects of NF1 disease. In more recent years we have narrowed our focus to the many tumors of the nervous system associated with this disease, all of which lack effective treatments.
Neurofibromas
These neural crest–derived tumors can be manifested within nerve plexuses (plexiform neurofibromas) where they can grow to enormous dimensions and disfigure, impair normal organ function, and transform into malignant tumors. They can also manifest as dermal neurofibromas that can cause disfigurement and great discomfort, and affect quality of life. We have successfully modeled these tumors and gained considerable information into their natural history, the role of the microenvironment, and insights into therapeutic strategies. More recently we have succeeded in culturing these tumors from mice. The availability of primary cultures will enable us to develop preclinical studies and to manipulate the cells genetically in unprecedented ways as a means of identifying novel targets for therapy.
Malignant peripheral nerve sheath tumors
Plexiform neurofibromas are thought to be the source of malignant peripheral nerve sheath tumors (MPNST), a form of sarcoma that is highly metastatic and incurable. Through the development of mouse models, we have identified critical novel pathways for tumor progression including the CXCR4 chemokine receptor. We have further recently developed tissue culture protocols that permit us to expand these tumors cells as primary cultures for more detailed studies. Having identified the progenitors responsible for these tumors within neurofibromas, we are actively seeking the CSC responsible for propagation of MPNSTs.