Harvard: A team led by Harvard Medical School researchers at Boston Children’s
Hospital has, for the first time, visualized the origins of cancer from
the first affected cell and watched its spread in a live animal.The researchers’ work, published in the Jan. 29 issue of Science,
could change the way scientists understand melanoma and other cancers
and could one day lead to new, early treatments 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,” said the paper’s first author, Charles Kaufman, HMS instructor in medicine at Dana-Farber Cancer Institute and a postdoctoral fellow in the Zon Laboratory at Boston Children’s Hospital.
“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,” said Kaufman.
That change, Kaufman and colleagues found, involves a set of genes that could be targeted to stop cancer from ever starting.
The study imaged live zebrafish over time to track the development of melanoma.
All the fish had the human cancer mutation BRAFV600E, found in most benign moles, and also had lost the tumor suppressor gene p53.
Kaufman and colleagues engineered the fish so that individual cells would light up in fluorescent green if a gene called crestin
was turned on—a “beacon” indicating activation of a genetic program
characteristic of stem cells. This program normally shuts off after
embryonic development, but occasionally, for reasons not yet known, crestin and other genes in the program turn back on in certain cells.
“Every so often we would see a green spot on a fish,” said the study’s senior investigator, Leonard Zon,
professor of stem cell and regenerative biology in the Faculty of Arts
and Sciences at Harvard University and director of the Stem Cell Program
at Boston Children’s. “When we followed them, they became tumors 100
percent of the time.”
Caught in action
When Kaufman, Zon and colleagues looked to see what was different about these early cancer cells, they found that crestin
and the other activated genes were the same ones turned on during
zebrafish embryonic development—specifically, in the stem cells that
give rise to the pigment cells known as melanocytes, within a structure
called the neural crest.
“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.”
Finding these cancer-originating cells was tedious. Wearing goggles
and using a microscope with a fluorescent filter, Kaufman examined the
fish as they swam around, shooting video with his mobile phone. Scanning
50 fish could take two to three hours.
In 30 fish, Kaufman spotted a small cluster of green-glowing cells
about the size of the head of a Sharpie marker. In all 30 cases, these
grew into melanomas. In two cases, he was able to see a single
green-glowing cell and watch it divide and ultimately become a tumor
mass.
“It’s estimated that only one in tens or hundreds of millions of
cells in a mole eventually become a melanoma,” said Kaufman. “Because we
can also efficiently breed many fish, we can look for these very rare
events. The rarity is very similar in both humans and fish, which
suggests that the underlying process of melanoma formation is probably
much the same in humans.”
Zon and Kaufman believe that their findings could lead to a new
genetic test for suspicious moles to see whether the cells are behaving
like neural crest cells, indicating that the stem cell program has been
turned on.
They are also investigating the regulatory elements that turn on the
genetic program, known as super-enhancers. These DNA elements have
epigenetic functions that are similar in zebrafish and human melanoma
and could potentially be targeted with drugs to stop a mole from
becoming cancerous.
A paradigm shift for cancer?
Zon and Kaufman posit a new model for cancer formation, going back to
a decades-old concept called field cancerization. They propose that
normal tissue becomes primed for cancer when oncogenes are activated and
tumor suppressor genes are silenced or lost, but that cancer develops
only when a cell in the tissue reverts to a more primitive, embryonic
state and starts dividing. They believe this model may apply to most—if
not all—cancers, not just melanoma.
The study was supported by the National Cancer Institute (R01
CA103846) and the National Institute of Arthritis and Musculoskeletal
and Skin Diseases (K08 AR061071) of the National Institutes of Health,
the Ellison Foundation, the Melanoma Research Alliance, the V Foundation
for Cancer Research and the Howard Hughes Medical Institute. Leonard
Zon is a co-founder and stockholder of Fate Therapeutics and Scholar
Rock.