Medical Student Research Fellowship for Summer 2011
Mentor: Lu Q. Le, M.D., Ph.D.
Department: Dermatology and Developmental Biology
Room number: NB5-226A
Mail Code: 9069
Phone number: 214-648-1157
Project title: NF1-Associated Dermal Neurofibromas: Cell of Origin, Progression and Therapeutics
Human subjects IRB approved project number (where applicable): IRB# 102009-039
Animal subjects IRB approved project number (where applicable): N/A for this project
Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects): patient-based research
Brief Description of Project:
The tumor predisposition disorder von Recklinghausen’s Neurofibromatosis type I (NF1) is one of the most common genetic disorders of the nervous system, affecting one in 3,500 individuals worldwide. Current treatment options for NF1 are primarily limited to surgery and longitudinal surveillance. NF1 patients have a wide spectrum of clinical presentations, including developmental, pigment or neoplastic aberrations of the skin, nervous system, bones, endocrine organs, blood vessels and the eyes. Neurofibromas, the most frequent tumors in NF1, and malignant nerve tumors are a serious complication of NF1. Plexiform neurofibroma is long thought to derive from the embryonic Schwann cell lineage. However, the identification of multipotent neural stems cells at later developmental stages in mouse and human raised the question of whether dermal neurofibromas might arise from early stages of Schwann cell progenitor/adult stem cells. Based on Knudson’s two-hit hypothesis, a second mutation in the inherited wild-type allele, at these early stages of Schwann cell differentiation, would initiate tumor development. However, little is known about the molecular mechanisms mediating the initiation and progression of these complex tumors, or the identity of the specific cell type that gives rise to dermal or cutaneous neurofibromas.
Recently, we identify a population of stem/progenitor cells residing in the dermis termed Skin-Derived Precursors (SKPs) as the cell of origin of NF1-associated dermal neurofibromas. We show that Nf1-deficient SKPs can give rise to classic plexiform or dermal neurofibromas contingent on their local microenvironment and exhibit the same properties as the embryonic Schwann cell progenitors that give rise to plexiform neurofibromas. Furthermore, we show that loss of Nf1 in SKPs is required but not sufficient to induce tumors and pointing to the essential role for the tumor microenvironment, including neurons and hormones, in neurofibroma development (Le et al., 2009).
The goals of this project are two folds: First, we will translate our findings in the laboratory into developing human clinical trial to treat dermal neurofibromas in NF1 patients. Because mast cells have been showed to be absolutely essential for neurofibroma genesis, we predict that different potent mast cell inhibitors will block neurofibroma formation in vivo. In fact, recent studies using bone marrow adoptive transfer have unequivocally showed the absolute required role of mast cells in neurofibroma tumor formation (Yang, 2008). Based on these observations, a single NF1 patient was treated with Gleevec (a mast cell inhibitor via c-kit inhibition) for airway compression by a plexiform neurofibroma resulting in a > 50% reduction in tumor size within 3 months of therapy and relief of airway compression. The patient has suffered no ill effects from therapy to date and continues to do well clinically. Because of these promising results, we are currently developing a clinical trial to treat dermal neurofibromas in NF1 patients with Gleevec.
Second, we propose establish an NF1 human tissue repository at UTSW to identify the cell of origin of human dermal neurofibroma and to elucidate factors such as hormones in the tumor microenvironment that regulate the evolution of neurofibroma from the stem/progenitor cells.
Le, L.Q., Shipman, T., Burns, D.K., Parada, L.F. (2009). Cell of origin and microenvironment contribution for NF1-associated dermal neurofibromas. Cell Stem Cell. 4 (5): 453-463.
Yang, F.C., Ingram, D.A., Chen, S., Zhu, Y., Yuan, J., Li, X., Yang, X., Knowles, S., Horn, W., Li, Y., et al. (2008). Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow. Cell 135, 437-448.
Previous Research Activities or Publications with Medical Students:
Rebecca would be the first medical student in my lab. However, I’ve worked with many graduate students, dermatology residents as well as post doctoral fellows.