David E. Fisher, MD, PhD
Chief, Department of Dermatology
Mass General Hospital
Harvard Medical School
55 Fruit Street
Our group studies cell death/proliferation signals in relation to development and disease, particularly in cancer of pigment cells (melanoma) and tumors of childhood. We attempt to understand critical modes of cell homeostasis with a goal of molecular targeted therapy as well as prevention of melanoma and other human cancers.
1) Lessions for malignancy from normal development. We study biology of melanocytes as a means of identifying pathways which drive melanoma in man. This includes examination of mechanisms underlying growth/survival of benign moles, most of which contain mutations in either BRAF or N-Ras oncogenes. We also study melanocyte death in hair follicles, a process associated with hair graying. Pathways were identified which link graying to melanocyte and melanoma survival, offering potential leads for novel therapies. Other studies focus on pathways modulating melanocytic responses to environmental cues and employ oncogene-transformed melanocytic lines which exhibit growth factor independence, mimicking human melanoma in a genetically controlled manner.
2) Control of life and death in melanoma. Malignant transformation of melanocytes produces one of the most treatment resistant malignancies in man. We have identified a transcriptional network which regulates melanoma cell survival and proliferation as well as melanocyte differentiation during development. Using diverse methods including mouse models, human tumor expression arrays, and cellular assays, we examine mechanisms through which melanoma cells evade death, with the goal of improving therapy. Studies include preclinical and clinical analyses of novel melanoma treatments. We also study the role of UV in pigmentation responses and carcinogenesis.
3) MITF transcription factor family in development & cancer. Mitf is a helix-loop-helix factor homologous to Myc, whose mutation in man produces absence of melanocytes. Mitf acts as a master regulator of melanocyte development and is targeted by several critical signaling pathways. Recently, members of the Mitf family have been discovered as oncogenes in a variety of human malignancies, particularly sarcomas of childhood. Their roles in cancer as well as strategies to target them therapeutically are under active investigation. Detailed mechanistic studies focus on transcription factor interactions with chromatin, particularly positioned nucleosomes.
- D’Orazio JA, Nobuhisa T, Cui R, Arya M, Spry M, Wakamatsu K, Igras V, Kunisada T, Granter SR, Nishimura EK, Ito S, Fisher DE. Critical role for MC1R in UV tanning: molecular mimicking and skin protection. Nature 2006 443(7109):340-4.
- Ozsolak F, Song JS, Liu XS, and Fisher DE. Global chromatin structure mapping of human promoters. Nature Biotechnology. 2007 25(2):244-8.
- Cui R, Widlund HR, Feige E , Lin JY, Wilensky DL, Igras VE, D’Orazio J, Fung CY, Schanbacher CF, Granter SR, and Fisher DE. The suntan response: p53 transactivation of POMC/MSH and its mimicking in skin diseases. Cell 2007 9;128(5): 853-64 2007.
- Lin, J and Fisher DE. Melanocyte biology and skin pigmentation. Nature. 2007 Feb 22;445(7130):843-50.
- Levy C, Khaled M, Robinson KC, Veguilla RA, Chen PH, Yokoyama S, Makino E, Lu J, Larue L, Beermann F, Chin L, Bosenberg M, Song JS, Fisher DE. Lineage specific transcriptional regulation of DICER by MITF in melanocytes. Cell In press.
For a complete listing of publications on PubMed, click here.
BBS webpage updated 6/15/2010