DF/HCC Program Affiliation

Cutaneous Oncology and Melanoma, Co-Leader
Cancer Genetics
Cancer Cell Biology

Research Abstract

Our lab focuses on two areas: analysis of a lineage specifying transcription factor, Microphthalmia; and mechanisms of p53-dependent apoptosis. Microphthalmia is a helix-loop-helix transcription factor which is essential to normal melanocyte, osteoclast, and mast cell development and function. We have identified its role as a major signaling intermediate in pathways activated by Steel/c-Kit, M-CSF/c-fms, and melanocyte stimulating hormone. Its expression and function may also be of importance in melanoma growth and has now been shown to be of considerable diagnostic utility. Our studies on p53 and apoptosis revolve around the importance of the p53 tumor suppressor in mediating a decision between growth arrest and apoptotic death following cellular stress. Because of its unique ability to trigger arrest in untransformed fibroblasts vs. apoptosis in oncogene transformed fibroblasts, its function offers a built in therapeutic window for tumor selective killing. To understand the mechanistic basis for its apoptotic activity we have devised a cell free system in which p53 protein appears to trigger a cascade resulting in caspase activation. Cellular extracts are being fractionated and the apoptotic intermediates are being isolated. This strategy has also uncovered potential inhibitory activities in extracts from certain tumors. The identification and characterization of these factors may add to our understanding of the regulation of cancer cell death and provide potential therapeutic targets.

Publications

• Cui R, Widlund HR, Feige E, Lin JY, Wilensky DL, Igras VE, D'Orazio J, Fung CY, Schanbacher CF, Granter SR, Fisher DE.Central role of p53 in the suntan response and pathologic hyperpigmentation.Cell 2007 Mar 9;128(5):853-64.
  17350573
• Lin JY, Fisher DE.Melanocyte biology and skin pigmentation.Nature 2007 Feb 22;445(7130):843-50.
  17314970
• Tsuda M, Davis IJ, Argani P, Shukla N, McGill GG, Nagai M, Saito T, Laé M, Fisher DE, Ladanyi M.TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition.Cancer Res
  17283122
• Ozsolak F, Song JS, Liu XS, Fisher DE.High-throughput mapping of the chromatin structure of human promoters.Nat Biotechnol 2007 Feb;25(2):244-8.
  17220878
• Chang EJ, Kim HJ, Ha J, Kim HJ, Ryu J, Park KH, Kim UH, Lee ZH, Kim HM, Fisher DE, Kim HH.Hyaluronan inhibits osteoclast differentiation via Toll-like receptor 4.J Cell Sci 2007 Jan 1;120(Pt 1):166-76.
  17164294
• 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.Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning.Nature 2006 Sep 21;443(7109):340-
  16988713
• Chin L, Garraway LA, Fisher DE.Malignant melanoma: genetics and therapeutics in the genomic era.Genes Dev 2006 Aug 15;20(16):2149-82.
  16912270
• Levy C, Khaled M, Fisher DE.MITF: master regulator of melanocyte development and melanoma oncogene.Trends Mol Med 2006 Sep;12(9):406-14.
  16899407
• Garraway LA, Weir BA, Zhao X, Widlund H, Beroukhim R, Berger A, Rimm D, Rubin MA, Fisher DE, Meyerson ML, Sellers WR."Lineage Addiction" in Human Cancer: Lessons from Integrated Genomics.Cold Spring Harb Symp Quant Biol 2005;70:25-34.
  16869735