David Fisher, M.D., Ph.D.


Head of the Department of Dermatology at Massachusetts General Hospital
Harvard Medical School
Edward Wigglesworth Professor of Dermatology
Harvard Medical School
Chair
Executive Committee on Research (ECOR), Massachusetts General Hospital
PhD Rockefeller University 1984
MD Weill Cornell Medical College 1985
epigenetics; hepatocyte growth factor; melanocytes; melanoma; microphthalmia-associated transcription factor; pathology; proto-oncogene proteins c-met; sarcoma clear cell; skin cancer; skin pigmentation; ultraviolet rays; vitamin d

Lesions 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.

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, since this potentially offers novel approaches to skin cancer prevention.

Mitf Transcription Factor Familty in Development and 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.