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Study of Cancer’s Origins Reveals Genetic Reprogramming of Single Cells

, by NCI Staff

Zebrafish in the laboratory of Leonard Zon, M.D.

Credit: Boston Children’s Hospital / Leonard Zon, M.D.

Researchers have created a model of cancer in zebrafish that allows them to capture live images of tumors forming and growing, in some cases from a single cell. Using the model, the researchers characterized some of the early genetic and epigenetic changes associated with melanoma, the most deadly form of skin cancer.

In the fish, an important event in the development of melanoma was the activation, in differentiated pigment-producing cells, of a genetic program that normally occurs during embryonic development. The reprogramming of these mature cells, called melanocytes, gave them some of the characteristics of stem cells , such as the ability to grow and divide frequently, the researchers found.

Charles Kaufman, M.D., Ph.D., of Boston Children’s Hospital, and his colleagues reported their findings in Science on January 29. The model relies on a fluorescent protein to mark cells that have been reprogrammed, allowing the investigators to observe the origins of cancer.

“With the zebrafish model, we were able to directly witness mature cells reverting back to a stem-cell stage,” said Leonard Zon, M.D., who directs the Stem Cell Research Program at Boston Children’s and led the study. “This [reprogramming] was ultimately devastating in terms of the development of cancer in the zebrafish.”

The fish had been engineered to carry two genetic changes in their melanocytes that are frequently found in human melanomas: the V600E mutation in the BRAF gene, which is also found in most benign moles, and the loss of a gene called p53, which helps suppress tumors.

Although all the melanocytes carried these changes, the zebrafish developed only one to three melanoma tumors. The reason, the researchers found, was that a third event—the genetic reprogramming—was required to transform melanocytes into cells that would develop into cancer.

“The findings suggest that the reprogramming of mutated cells into a less mature state may be important in tumor development,” said Steven X. Hou, Ph.D., of NCI’s Center for Cancer Research (CCR), who investigates stem cells and tumor-initiating cells but was not involved in the study.

Cancer researchers know that certain genetic mutations promote tumors, but much remains to be learned about how a single cell that carries such mutations becomes transformed and how tumors arise, noted Dr. Hou. “The cell-labeling method developed using zebrafish will be a powerful tool for analyzing the development of tumors in vivo,” he added.

The study results could also lead to new ways of diagnosing melanoma based on the genetic signatures associated with the transformation of mutated skin cells, the study authors noted. And understanding the mechanisms underlying the transformation may allow researchers to explore ways to target them.

Finding a Marker of Transformation

When the project began in Dr. Zon’s lab a decade ago, the goal was to find ways to detect a melanoma in zebrafish with the BRAF and p53 mutations before a bump (indicating the presence of melanoma) became visible.

An important advance came when the researchers discovered that a gene called crestin, which is expressed in a structure called the neural crest during early embryonic development and is then turned off, was expressed in large melanoma tumors in zebrafish. To capitalize on this discovery, Dr. Kaufman and his colleagues engineered the fish to express a fluorescent green protein each time that crestin was switched on in adult cells.

“An amazing moment in this study was seeing cancer when it was a single cell,” said Dr. Kaufman. “At that point, the change in the cell—the reprogramming—had occurred,” he added.

Over the course of 2 weeks, the researchers could watch as single genetically reprogrammed melanocytes divided to become small patches of transformed cells. Every melanocyte that expressed crestin in the study progressed to a melanoma.

Crestin is spectacularly useful as a marker in fish,” said Glenn Merlino, Ph.D., a CCR investigator who studies melanoma and also had no role in the research. “This study shows us where the melanoma cells come from and allows us to see aspects of the process that we could not otherwise see.”

Previous studies have suggested that activation of embryonic genetic programs may play a role in cancer, but it has not been clear when this reprogramming might occur in the development of tumors. The new findings suggest that it may occur very early in the onset of cancer, the study authors said.

“The next step is to understand how this process starts,” said Dr. Kaufman. “The transformed cells were responding to a distinct signal that was pushing them back to an earlier stage of development.”

Although the precise mechanisms that control the genetic reprogramming of melanocytes in the zebrafish are not yet known, the researchers did find some clues. They identified a chromosome region containing genes that regulate crestin during embryonic development and melanoma formation, including one called sox10. A human version of sox10 is expressed at abnormal levels in human melanomas, the researchers noted.

A Change of Fate

The model raises a fundamental question about cancer that it could potentially help answer: Why do some cells that harbor cancer-related genetic mutations never progress to tumors? The majority of benign moles, for example, carry a BRAF mutation that is found in most melanomas, yet these moles rarely progress to cancer. In the zebrafish, melanomas were also a rare occurrence, even though all the melanocytes contained BRAF and p53 mutations.

“With the expression of the crestin gene in the zebrafish cells, there was a very specific switch from a mature cell to a less mature cell,” noted Dr. Merlino. “This gave the cells some of the plasticity that stem cells have but that mature cells do not.”

For Dr. Zon, the switch represents a change in the identity, or fate, of a cell. The fate change in the zebrafish melanocytes also highlights potential similarities between how tumors arise and the development of tissues in the body, he added.

“The process of stem cells giving rise to the body’s tissues seems to be recapitulated in cancer,” Dr. Zon continued. “By studying developmental biology—and, specifically, how organs develop—we may learn a lot about cancer.”

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