BRAF Signaling in Cancer and Development in Zebrafish

Summary

Melanoma is the most deadly form of skin cancer, resulting in the premature death of almost 2000 people each year in the UK alone. Melanoma can develop is from nevi: highly common and benign tumours of melanocytes, prevented from becoming neoplastic by activation of senescence. While a normal cell reaches senescence as it ages, it is now understood to act as a protective mechanism against cancer as well. Thus, understanding the mechanism whereby cells can sense early cancer events, and then initiate senescence, is of critical importance for our understanding of melanoma - and all cancer development - and design of future therapies.

The Gene-Environment Interface

1. Our goal is to identify new genes that confer risk of melanoma development after exposure to UV-irradiation.

We aim to

1. follow the pathological effects of UV-treatment on fish neavi and melanoma transformation
2. generate a UV-induced mole-to-melanoma model in zebrafish
3. perform a genetic screen for mutations that confer risk to BRAF-mutant melanoma.

Our long-term vision is to use the UV model of melanoma to understand how cancer genetics interfaces with environmental carcinogens, and to identify new gene targets of melanoma susceptibility and drug design.

BRAF in Development

Recently, the perception of the MAPK-signaling pathway genes as only 'cancer-genes' has been dramatically altered by the discovery that germ-line mutations in BRAF and MEK are the cause of cardio-facial-cutaneous (CFC) syndrome. We are using zebrafish to understand the normal developmental function of BRAF, MEK1/2; the phenotypes imposed by CFC BRAF and MEK alleles; and to test the effects of chemical inhibitors on the activity of the CFC alleles. In this way, we strive to gain insight into how BRAF signaling contributes to the complex three-dimensional development of the embryo.

Lab Members

Current lab members involved in this work are:

• Dr Elizabeth Patton
• Dr Hironori Ishizaki (MD)
• Dr Zhiqiang Zeng
• Dr Nicholas Temperley
• Jennifer Richardson
• Kerrie Taylor
• Karthikeyani Paranthaman
  
  

1. Melanocyte Development and Melanoma (Edinburgh Cancer Research Centre)

2. BRAF Signaling in Cancer and Development in Zebrafish (this page)

Melanoma is the most deadly form of skin cancer, resulting in the premature death of almost 2000 people each year in the UK alone. Melanoma can develop is from nevi: highly common and benign tumours of melanocytes, prevented from becoming neoplastic by activation of senescence. While a normal cell reaches senescence as it ages, it is now understood to act as a protective mechanism against cancer as well. Thus, understanding the mechanism whereby cells can sense early cancer events, and then initiate senescence, is of critical importance for our understanding of melanoma - and all cancer development - and in the design of future therapies.

While in the Zon lab (Children's Hospital Boston, Harvard Medical School), we developed a mole-to-melanoma zebrafish model of cancer progression based on the most frequently mutated human gene in melanoma, BRAF. Significantly, with the loss of p53, a major regulator of senescence, melanoma rapidly develops. Because of the highly similar genetic and cancer pathology between humans and fish, the BRAF-fish are a unique starting point for identifying novel genes, environmental conditions, and therapeutic compounds that control senescence and the mole-to-melanoma transition.

Links

Zebrafish Movies: Dr Amy Mitchell, Mini-project (note:this section requires a password).