Research Profile: Colin Goding, Ph.D., LICR Oxford Branch
Dr. Colin Goding
Dr. Colin Goding, formerly head of the Signaling and Development Group at the Marie Curie Research Institute (MCRI) in Oxted, UK, joined the Oxford Branch as a Member on January 8th with six of his current team members (four post-doctoral fellows, a clinical research fellow and a PhD student). Through more than twenty years of research on malignant melanoma—a cancer that is increasingly common and particularly dangerous since it easily metastasizes—Dr. Goding and his colleagues have established effective strategies to investigate how changes in the cell’s gene regulation programs lead to the onset and progression of cancer.
Dr. Goding grew up in the UK and earned his PhD in virology from the National Institute for Medical Research at the Medical Research Council in London. With a fellowship from the Royal Society, he then moved to Strasbourg in France for his post-doctoral work in the laboratory of Dr. Pierre Chambon at the Institute of Genetics and Molecular and Cellular Biology. In 1985, he came back to the UK to set up his research group at the MCRI.
Exploring Melanocytes & Melanoma
To understand how melanoma tumors develop, Dr. Goding’s team takes advantage of studies in both melanoma cells and melanocytes, a type of skin cell that produces the pigment melanin and in which the cancer originates. “We are interested why melanomas are so resistant to tharapy, and why melanomas metastasize so rapidly, which is most likely related to the ability of melanoblasts [immature melanocytes] to migrate,” Dr. Goding says. He explains that tumor progression and metastasis are intimately linked with embryonic development. As particular gene regulation programs are activated, immature melanocytes leave an embryonic structure called the neural crest and migrate throughout the embryo to form mature melanocytes in the skin and hair follcles. It appears that the same signaling pathways that turn on these programs during development are de-regulated in cancer.
Melanocytes offer a convenient model system for studies of normal development since mutations that affect their lineage produce a distinct coat color in mice without affecting the animals’ viability. Melanoma, on the other hand, is an ideal model disease to study tumor progression since it can be diagnosed early: tumors of all stages, from benign to metastatic disease, are available for analysis. “The melanocyte-melanoma system,” says Dr. Goding, “allows us to relate key events that occur in the entire progression from the neural crest, through the development of melanoblasts, melanocytes and melanocyte stem cells, to the origins and progression of malignant melanoma.”
A Switch on Melanoma Cells
Melanoma kills many of its victims owing to the capacity of tumors to metastasize and develop resistance to chemotherapy, which today is the prevalent treatment for the metastatic disease. With the goal of finding more effective therapies, Dr. Goding’s team tries to understand how melanoma tumors can adapt their behavior in response to changes in their local environment.
A breakthrough came a few years ago when the team discovered that a transcription factor (protein that regulates the transfer of genetic information from DNA to RNA) named Mitf acts as a master switch of melanoma behavior. Mitf was found to be expressed at different levels among tumor cells and to play a role in various processes including cell division, differentiation (the process whereby cells become specialized), migration, and metastasis. “Mitf is expressed in melanomas in a mutually exclusive fashion with the transcription factor Brn-2, which appears to repress Mitf expression,” Dr. Goding explains. “Strikingly, Mitf positive cells proliferate or differentiate, whereas Mitf-negative cells adopt a stem-cell like phenotype and are highly invasive.”
If tumor cells can adapt their behavior by bringing Mitf levels up or down, it may be possible to design drugs that prevent tumor progression by targeting factors that control the expression or activity of Mitf. Therefore, the current effort of the team is to determine how Brn-2, and other proteins, regulates Mitf.
Cells in this melanoma tumor express the transcription factors Mitf (green) and Brn-2 (red) in a mutually exclusive manner.
Restoring Senescence in Tumors
A few years ago, Dr. Goding’s team embarked on exploring senescence, a phenomenon that controls how many times a cell can divide. Normal cells duplicate around 50 times, after which they enter senescence and stop dividing. Tumor cells, however, typically bypass senescence to gain a limitless potential to divide.
Dr. Goding and colleagues found that two transcription factors, Tbx2 and Tbx3, are implicated in turning off senescence in melanoma. Their findings suggest that inhibition of these factors could restore senescence in tumor cells, raising the prospect of novel treatments for melanoma that act by inducing senescence. A major challenge, however, is to find ways of blocking the activities of Tbx2/3 in real tumors. One potential strategy would be to target the signaling pathways that control the expression of Tbx2/3, while another would be to target proteins that directly control the activity of these factors. Both possibilities are now being explored by the team, with the long-term goal of finding ways to re-activate tumor senescence in melanoma patients.
Gene Regulation in Yeast
Beside melanocytes and melanoma cells, Dr. Goding and his colleagues use the yeast Saccharomyces cerevisiae to explore the fundamental mechanisms of gene regulation. In particular, they hope to learn how specific nutritional signals trigger the sequential binding of transcription factors to promoters (start sites of gene transcription) and, accordingly, enable the recruitment of enzymes that remodel the structure of chromatin (the complex of DNA and proteins that makes up chromosomes). Since similar mechanisms are involved in the regulation of mammalian genes, studies performed in yeast cells—which are relatively easy to manipulate—can clarify how human genes become deregulated in cancer. “We are particularly focused on understanding how transcription complexes make and break gene loops and the role of natural anti-sense transcription in this process,” Dr. Goding says. “This is a relatively new field, but has wide implications for how genes are regulated. We will use the information provided to understand better how key melanocyte- and melanoma associated genes are regulated in development and in tumor formation.”
Suggested Reading- Moreau, J-L., Lee, M., Mahachi, M., Vary, J., Mellor, J., Tsukiyama, T., and Goding, C.R. (2003) Regulated displacement of TBP from the PHO8 promoter in vivo requires Cbf1 and the Isw1 chromatin remodeling complex. Molecular Cell, 11,1609-1620.
- Prince, S. Carreira, S., Vance, K. and Goding C.R. (2004) The p21Waf-1 promoter is a direct target for Tbx2. Cancer Res. 64, 1669-1674.
- Martinez-Campa, C, Politis, P., Moreau, J.-L., Kent, N., Goodall, J., Mellor, J. and Goding C.R. (2004) Precise nucleosome positioning and the TATA box dictate requirements for the histone H4 tail and the bromo-domain factor Bdf1. Molecular Cell 15, 69-81.
- Carreira, S., Goodall, J., Aksan, I., La Rocca, S.A., Galibert, M.-D., Denat, L., Larue, L. and Goding, C.R. (2005) Mitf cooperates with Rb1 and activates p21Cip1expression to regulate cell cycle progression. Nature 433, 764-769.
- Carreira, S., Goodall, J. Denat, L., Rodriguez, M., Nuciforo, P, Hoek, K.S., Testori, A., Larue, L. and Goding, C.R. (2006) Mitf regulation of Dia1 controls melanoma proliferation and invasiveness. Genes & Dev 20, 3426-3439.