Science offers a new idea of cancer: the perfect combination of genetic alterations that tumors use to promote explosive growth and prevent their own death

Scientists at the University of Pittsburgh School of Medicine have discovered the missing piece of the puzzle in the mystery of how melanoma controls its mortality
.

This week, Dr.
Jonathan Alder and his team described how they discovered the perfect combination of genetic alterations that tumors use to promote explosive growth and prevent their own death, a development that could change the way
oncologists understand and treat melanoma.

Alder, an assistant professor in the Department of Medicine at Pitt Medical School, said: "What we do is inherently obvious, based on previous basic research and connected
to what happens to patients.
"

Telomeres are protective caps at the ends of chromosomes and are necessary to
prevent DNA degradation.
In healthy cells, telomeres become shorter with each replication cycle until they are short enough for the cells to no longer divide
.
Disruption in the maintenance of telomere length can lead to serious disease
.
Short telomere syndrome causes premature aging and death, but extra-long telomeres have been linked to
cancer.

Over the years, scientists have observed amazingly long telomeres in melanoma, especially when compared to
other cancer types.

"There are some special links
between melanoma and telomere maintenance," Alder said.
"One of the biggest obstacles for a melanocytes to transform into cancer is making itself immortal
.
Once it can do that, it's on its way
to cancer.
”

Telomerase proteins are responsible for lengthening telomeres, protecting them from damage and preventing cell death
.
Telomerase is inactive in most cells, but many types of cancer take advantage of mutations in the telomerase gene TERT to activate this protein and allow cells to continue growing
.
Melanoma is particularly well-known
in this regard.

About 75% of melanoma tumors contain mutations in the TERT gene, which stimulate protein production and increase telomerase activity
.
However, when scientists mutated TERT in melanocytes, they were unable to produce the same long telomeres seen in patients' tumors
.
As it turns out, the TERT promoter mutation is only half the
story.

Dr.
Pattra Chun-on, an internist who received his doctorate in Auld's lab, was determined to find the missing link
between melanoma, mutations in the TERT promoter, and long telomeres.

Alder said: "The interesting thing about this story is that Pattra joined my lab
.
She contacted me and told me she was interested in
studying cancer.
I told her I was studying short telomeres instead of long telomeres
.
This continued until I realized that Pattra would never accept a 'no' answer
.
”

In combing through the cancer mutation database, Alder's lab team previously identified a region in the telomere-binding protein TPP1, which is often mutated
in melanoma.

When Pattra discovered in the lab that the mutation in TPP1 was strikingly similar to that of TERT, her determination shone through; They are located in the newly annotated TPP1 promoter region and stimulate protein production
.
Auld is excited because TPP1 has long been thought to stimulate telomerase activity
.

"As early as more than a decade ago, biochemists discovered that TPP1 could increase telomerase activity in test tubes, but we never knew this actually happened clinically
," he said.

When the researchers added mutated TERT and TPP1 back into the cells, the two proteins worked synergistically to produce the unique long telomeres
visible in melanoma.
TPP1 is the missing factor that scientists have been looking for, and it has always been hidden under
people's noses.

The discovery has changed scientists' understanding of the pathogenesis of melanoma, but it also has the potential to improve treatment
.
By identifying the cancer-specific telomere maintenance system, scientists have a new therapeutic target
.