“More and more data suggest that just having mutations is not sufficient to cause cancer,” said Dr. Kornelia Polyak, a breast cancer researcher at the Dana-Farber Cancer Institute, who was not associated with the new study. “You need the right context.”

That was where Dr. Zon and his colleagues began 10 years ago. They were investigating melanoma by creating it in zebra fish, tiny transparent creatures that allow researchers to see cells and organs without cutting the fish open. The researchers put human BRAF and P53 genes in every melanocyte, the pigmented skin cells, of the fish. If genes were all that was needed for cancer, the fish would explode with melanoma. But the researchers found only one to three melanomas per fish.

“That told us there has to be an additional event,” Dr. Zon said.

By luck, they found it. The pigmented skin cells that became cancerous had turned on a gene, crestin, that is normally activated only in cells that are part of the neural crest, a group of cells pinched off early in embryonic life from a region adjacent to the brain. These primitive cells, depending on where they are in the embryo, can turn into pigmented skin cells or a variety of other types of cells, like those that make up bones and teeth, the covering of the brain or those that sheath and insulate nerve cells. Once cells develop into their mature tissue type — pigmented skin cell, bone or tooth, for example — the crestin gene shuts down. Those pigmented skin cells in the fish that had an active crestin gene had reverted to that primitive state when they were malleable, their fates still wide open.

The investigators marked cells with an active crestin gene with a fluorescent dye, enabling them to spot the cells because they glowed bright green. Then they observed what happened. Every time a cell lit up green it divided and turned into a cancer. Cells that did not light up never turned into a cancer.

That makes sense, Dr. Polyak said, because such primitive cells are more proliferative and more able to spread throughout the body. That is their role during development. They also can develop their own blood supply, something tumors do, too.

The zebra fish work was convincing, Dr. Ronai said. “They provide a pretty strong demonstration that that pathway is correct,” he said. “It’s a significant advance in the field.” It can, he said, allow researchers to monitor the early development of melanomas.