Melanoma Visualized in Live Zebrafish From Origin of First Cancer Cell To Metastasis
Could the humble zebrafish help clinicians visualize cancer?
Researchers visualized the origins of cancer from the first affected cell through its spread in a live animal: the zebrafish. This research, published in Science, may change scientific understanding of melanoma and other cancers leading to new treatments that can be administered early, before the cancer has taken hold.
"An important mystery has been why some cells in the body already have mutations seen in cancer, but do not yet fully behave like the cancer," explained Charles Kaufman, MD, PhD, a postdoctoral fellow in the Zon Laboratory at Boston Children's Hospital in Massachusetts, and first author of the paper. "We found that the beginning of cancer occurs after activation of an oncogene or loss of a tumor suppressor, and involves a change that takes a single cell back to a stem cell state."
The change in the set of genes found by this research team might be targeted to stop the start of cancer. This research investigated the early downstream molecular events required to reprogram normal cells into cancer cells, which are still poorly understood.
Live zebrafish were imaged over time to track the development of melanoma. The fish all had the BRAF V600E mutation, which occurs in human cancer and is found in most benign moles. The fish also had lost the tumor suppressor gene p53. They were engineered to light up fluorescent green when the gene crestin was turned on.
Crestin acted as a beacon that indicated the activation of a genetic program characteristic of stem cells. Normally, crestin turns off after embryonic development, but, in certain cells, crestin and other genes in the stem cell program turn back on.
"Every so often we would see a green spot on a fish," said senior investigator Leonard Zon, MD, director of the Stem Cell Research Program at Boston Children's. "When we followed them, they became tumors 100% of the time."
When these early cancer cells were examined, crestin and other activated genes were found to be the same genes that are turned on during zebrafish embryonic development. Specifically, these activated genes are in the neural crest structure in stem cells that give rise to melanocytes, which are pigment cells.
"What's cool about this group of genes is that they also get turned on in human melanoma," said Zon. "It's a change in cell fate, back to neural crest status."
Zon and Kaufman believe that their findings could lead to a new genetic test for suspicious moles. The test could aim to see whether the cells are behaving like neural crest cells, indicating that the stem-cell program has been turned on. The researchers are also investigating the regulatory elements that turn on the genetic program, known as super-enhancers. They feel potential exists to target the epigenetic function of these DNA elements to stop a mole from becoming cancerous.
A new model for cancer formation has emerged from this study, and it goes back to a decades-old concept of field cancerization. Zon and Kaufman propose that normal tissue becomes primed for cancer when oncogenes are activated and tumor suppressor genes are silenced or lost; however, cancer develops only when a cell in the tissue reverts to a more primitive, embryonic state and starts dividing. The authors stated that this model may apply to most if not all cancers, not just melanoma.
1. Kaufman CK, Mosimann C, Fan ZP, et al. A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation [published online ahead of print January 28, 2016]. Science. 2016;351(6272):aad2197.