J. William Harbour, M.D.
Professor of Opthalmology
Description of Research
The Harbour Lab uses genetic, genomic and bioinformatic technology, cell culture experiments, and genetically modified animal models to understand mechanisms of tumor progression in major forms of eye cancer, including: uveal melanoma, retinoblastoma and intraocular lymphoma. All of these cancers are extremely aggressive and frequently fatal. The Lab discovered that primary uveal melanomas, the most common primary cancer of the eye, can be divided based on gene expression profiling into class 1 (low metastatic risk) and class 2 (high metastatic risk). This discovery has been translated into a clinical prognostic test that was validated in a prospective multicenter study and is now commercially available around the world. The vast majority of ocular oncology centers in the developed world now use this test for routine clinical testing.
Recently, Dr. Harbour’s lab discovered that inactivating mutations in the tumor suppressor gene BAP1 are strongly associated with class 2 tumors and metastasis. Further work has shown that histone deacetylase (HDAC) inhibitors can reverse the biochemical effects of BAP1 loss and may play a role in the clinical management of metastasis in these patients. Dr. Harbour’s lab also discovered that BAP1 mutations can be transmitted through the germline, resulting in a newly described BAP1 familial cancer syndrome. Patients with this syndrome transmit a BAP1 mutation in an autosomal dominant fashion, and are at risk for uveal and cutaneous melanoma, atypical cutaneous nevi, mesothelioma, meningioma, gastric cancer, lung and breast cancer, and other cancers. Since BAP1 regulates gene expression by deubiquitinating histone H2A, they are investigating the genes that are regulated by BAP1 using an integrated approach that involves RNA-seq and ChIP-seq technologies.
The Harbour laboratory is also exploring the role of cancer stem cells in the development of treatment resistance in both uveal melanoma and retinoblastoma. The location of his lab within the Interdisciplinary Stem Cell Institute creates many synergistic opportunities for applying stem cell culture methods to the understanding of cancer stem cells.
- Discovered driver mutations in the tumor suppressor gene BAP1 in uveal melanoma and showed that these mutations are tightly linked to metastatic death.
- Discovered driver mutations in the splicing factor SF3B1 in uveal melanoma and showed that these mutations are associated with good prognosis.
- Discovered that histone deacetylase inhibitors reverse the biochemical effects of BAP1 mutation and may have a role in targeted therapy of uveal melanoma metastasis.
- Discovered a gene expression signature that predicts metastasis in uveal melanoma. This discovery led to the development of a clinical test that is widely used.
Selected Cancer-Related Publications
- Asnaghi L, Handa JT, Merbs SL, Harbour JW, Eberhart CG. A role for jag2 in promoting uveal melanoma dissemination and growth. Invest Ophthalmol Vis Sci 54:295-306,2013 Read more »
- Dimaras H, Parulekar MV, Kwok G, Simpson ER, Ali A, Halliday W, Shago M, Harbour JW, Héon E, Gallie BL, Chan HS. Molecular testing prognostic of low risk in epithelioid uveal melanoma in a child. Br J Ophthalmol 97:323-6,2013 Read more »
- Harbour JW. Genomic,prognostic,and cell-signaling advances in uveal melanoma. Am Soc Clin Oncol Educ Book 2013:388-91,2013 Read more »
- Laurent C, Gentien D, Piperno-Neumann S, Némati F, Nicolas A, Tesson B, Desjardins L, Mariani P, Rapinat A, Sastre-Garau X, Couturier J, Hupé P, de Koning L, Dubois T, Roman-Roman S, Stern MH, Barillot E, Harbour JW, Saule S, Decaudin D. Patient-derived xenografts recapitulate molecular features of human uveal melanomas. Mol Oncol 7:625-36,2013 Read more »
- Harbour JW, Chen R. The DecisionDx-UM Gene Expression Profile Test Provides Risk Stratification and Individualized Patient Care in Uveal Melanoma. PLoS Curr 5:,2013 Read more »
- Harbour JW, Roberson ED, Anbunathan H, Onken MD, Worley LA, Bowcock AM. Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. Nat Genet 45:133-5,2013 Read more »
- Harbour JW, Wilson D, Finger PT, Worley LA, Onken MD. Gene expressing profiling of iris melanomas. Ophthalmology 120:213-213.e3,2013 Read more »
- Harbour JW. The genetics of uveal melanoma: an emerging framework for targeted therapy. Pigment Cell Melanoma Res 25:171-81,2012 Read more »
- Asnaghi L, Ebrahimi KB, Schreck KC, Bar EE, Coonfield ML, Bell WR, Handa J, Merbs SL, Harbour JW, Eberhart CG. Notch signaling promotes growth and invasion in uveal melanoma. Clin Cancer Res 18:654-65,2012 Read more »
- Harbour JW. A new mutation with staggering effects. Pigment Cell Melanoma Res 24:1081-2,2011 Read more »
Collaborating in the Multidisciplinary Research Program(s):