The scientists found the beginning of melanoma involves a change that takes a single cancer-prone cell back to a stem cell state.
The discovery - reported in a Science paper - could change the way we understand melanoma and other cancers, and could lead to drugs that prevent cancer by blocking the genes that trigger this key event.
It resolves a mystery that has been puzzling cancer researchers: why some cells in the body carry gene mutations - so-called oncogenes - seen in cancer but do not fully behave like cancer.
Melanoma, which starts in melanocytes - cells that make the melanin that gives skin its color - is a good example of this. The majority of skin moles bear cancer mutations in their melanocytes, but they rarely convert to melanoma.
First author Dr. Charles Kaufman, instructor in medicine at Harvard Medical School's Dana-Farber Cancer Institute in Cambridge, MA, says:
"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."
He and his colleagues say their evidence supports the idea of the "cancerized field" where cancer cells can be primed for cancer but do not actually become cancerous until a key event occurs. Their study shows this key event to be an extra step that takes a primed cell back to a stem cell state.
Zebrafish model overcomes challenges of studying origins of cancer
Studying how cancer begins in cells is challenging, say the researchers, because the emergence of the first tumor cell is rare, is not easy to visualize in living organisms, and once it emerges, it quickly expands to form the tumor mass.
To overcome these challenges, the team decided to use zebrafish. Dr. Kaufman says it is estimated that only one in tens or hundreds of millions of cells in a mole eventually forms a melanoma. But because they can breed many zebrafish, they can look for these rare events.
The team engineered zebrafish with two genetic features found in melanoma - the presence of the human cancer mutation BRAFV600E and the lack of the tumor suppressor gene p53.
They also engineered the fish so if a gene called crestin was switched on in any cell, that cell would glow a green fluorescent color.
A switched-on crestin gene signals that a genetic program that occurs in stem cells is active. The program is associated with the development of the "neural crest," a temporary group of cells that occurs in early embryonic development and gives rise to many different cell types, including melanocytes.
Crestin normally switches off after embryonic development, but sometimes - for reasons yet to be discovered - this and other genes in the program turn back on in certain cells.
Discovery could lead to genetic test to find suspect moles
The researchers spotted a small cluster of green-glowing cells in 30 of the fish they engineered. In all 30 cases, the clusters grew into melanomas.
Senior author Leonard Zon, professor of stem cell and regenerative biology at Harvard University and also of Boston Children's Hospital, says:
"Every so often we would see a green spot on a fish. When we followed them, they became tumors 100% of the time."
In two cases, the researchers saw a single green-glowing cell divide and eventually form a tumor mass. These observations show that having the crestin genes switched on is strongly linked to the birth of melanomas.
"What's cool about this group of genes," says Prof. Zon, "is that they also get turned on in human melanoma."
The researchers believe their discovery could lead to a new genetic test for suspicious moles that determines whether they contain cells that have the stem cell program turned on.
They are also investigating the DNA elements - called super-enhancers - that control the genetic program. These work epigenetically - they tag the DNA without altering the underlying code - in a similar fashion in zebrafish and human melanoma and could be potential targets for drugs that stop moles becoming cancerous.
In the following video, Prof. Zon gives an account of their study into the origins of cancer and their work with the zebrafish melanoma model:
Meanwhile, Medical News Today recently learned how another group of scientists has discovered another clue to how cancer tumors form. It appears that a small minority of cancer cells extend "cellular cables" to pull nearby cells - including a lot of healthy cells - into the early tumor mass.