Our laboratory research focuses on making life as difficult for the cancer cells as they do to us. To this end, we work on: (1) identification of the cell origin of tumorigenesis (how does certain type of cancers originated and developed from adult stem cell?); and (2) elucidating the roles of microenvironment in tumor development (how do neighboring non-cancerous cells dictate cancer development and progression?). We dissect these cellular and molecular mechanisms of tumorigensis from a developmental perspective. We use Neurofibromatosis Type I (Nf1), a common tumor predisposition human genetic disorder, as a model to address these two fundamental issues of cancer biology as well as elucidating cutaneous nervous system development and regeneration.
Nf1 is caused by mutation in the NF1 tumor suppressor gene, which encodes a GTPase Activating Protein (GAP) that negatively regulates p21-RAS signaling. Nf1 patients have defects in the Neural Crest-derived tissues, leading to 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 tumor in Nf1, and malignant nerve tumors are serious complication of Nf1. However, little is known about the molecular mechanisms mediating the initiation and progression of neurofibromas, as well as the cell of origin of dermal neurofibromas, the most common, disfiguring tumors in Nf1 patients. Our work demonstrates that the newly identified neural crest-related precursor cells in the skin are the cell of origin of dermal neurofibroma and provide compelling evidences that other factors and signals from the non-neoplastic cells in the tumor microenvironment play essential roles in neurofibroma genesis. As such, these models will provide a novel platform to test therapies for the disfiguring dermal and plexiform neurofibromas.
RESEARCH INTERESTS
Neurofibromatosis
Cancer Biology
Stem Cell Biology
RECENT PUBLICATIONS
Le, L.Q., Parada, L.F., "Tumor Microenvironment and Neurofibromatosis Type I: Connecting the GAPs" Oncogene, 26(32):4609-4616, 2007
Le, L.Q., Kabarowski, J., Wong, S., Nguyen, K., Gambhir, S., Witte, O.N., "Positron Emission Tomography Imaging Analysis of G2A as a Negative Modifier of Lymphoid Leukemogenesis Initiated by the BCR-ABL Oncogene" Cancer Cell, 1(4):381-391, 2002
Le, L.Q., Kabarowski, J., Weng, Z., Satterthwaite, A., Harvill, E., Jensen, E., Miller, J.F. and Witte, O.N., "Mice lacking the orphan G protein-coupled receptor, G2A, develop a late-onset autoimmune syndrome" Immunity, 14(5):561 - 571, 2001
Kabarowski, J.H.S., Feramisco, J.D., Le, L.Q., Gu, J.L., Luoh, S-W., Simon, M.I., and Wite, O.N., "The transcriptionally regulated orphan G protein-coupled receptor (G2A) elicits RhoA dependent actin rearrangement via G13" Proc. Natil. Acad. Sci. USA, 97:12109 - 12114, 2000
Weng, Z., Fluckiger, A., Nisitani, S., Wahl, M.I., Le, L.Q., Hunter, C.A., Fernald, A.A., Le Beau, M.M., and Witte, O.N., "A DNA Damage and Stress Inducible G Protein-Coupled Receptor Blocks cells in G2/M" Proc. Natil. Acad. Sci. USA, 95:12334 - 12339, 1998
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