Cancer scientists have long faced a conundrum: as the disease starts, there’s usually a group of cells sharing a mutation that makes them prone to forming cancer, yet only a few do so. So what’s so special, or different, about these cells? Scientists have just taken a step toward understanding this phenomenon, having for the first time watched cancer develop and spread from a single cell inside a live animal.

The focus of this study, published in Science, was melanoma, a rare but serious skin cancer that has its origins in pigment-producing cells called melanocytes. The disease often begins as a mole, but even benign moles more often than not actually contain cancer-causing (or oncogenic) mutations in a gene called BRAF^V600E, yet they rarely go on to form melanoma.

To investigate what else might be driving the initiation of cancer, researchers from Boston Children’s Hospital turned to the zebrafish, a model animal that’s easy to manipulate and track in the lab. They engineered the fish so that they had the human BRAF^V600E cancer gene in addition to a mutation in a so-called tumor suppressor gene called p53. As the name suggests, this gene normally serves to prevent the formation of tumors, but loss of its function through mutation is a common feature in cancer.

They were specifically interested in a gene called crestin which is active, or expressed during embryo development in a specific population of stem cells called neural crest progenitors. The neural crest is a transient structure that ultimately goes on to yield the cells that become neurons, bone, cartilage, and melanocytes, to name a few. Interestingly, crestin also gets reexpressed in melanoma tumors, although why this is is a mystery.

The researchers therefore made a further modification to the fish, adding in a gene that codes for a green fluorescent protein that would light up whenever crestin was expressed, allowing the researchers to track the development and progression of melanoma. After stalking these fish in a tank and imaging them live, the researchers found that each time a green patch emerged, indicating that crestin was switched on, this single fluorescent cell would go on to form a tumor.

^{Study author Leonard Zon with the zebrafish. Justin Ide}

Further analysis revealed that crestin-expressing, early tumor cells also show a gene expression pattern similar to what is observed during embryonic development, in neural crest cells. In other words, the cells that go on to form cancer experience a switch in cell fate that takes them back to a stem cell state. So while multiple cells may possess the right set of gene mutations to prime them for tumor development, it is only when one experiences a reversion back towards a more primitive state that cancer will form.

“It’s estimated that only one in tens or hundreds of millions of cells in a mole eventually become a melanoma,” lead author Dr. Charles Kaufman said in a statement. “Because we can so efficiently breed many fish, we can look for these very rare events. The rarity is very similar in humans and fish, which suggests that the underlying process of melanoma formation is probably much the same in humans.”

Although they’ve only shown this for melanoma, the team thinks this could be true for other types of cancer, but further investigations will be required to prove this.