A cell's identity depends on the levels of proteins it produces,
and these can be altered by changes in the way proteins are translated
from genetic instructions.
Each cell in the body follows a strict protocol for manufacturing the
proteins it needs to function. When a cell turns cancerous, however,
its protein production goes off script. A new study led by researchers
at The Rockefeller University takes a close look at one way in which
this procedure goes haywire in skin cells as they turn cancerous.
‘One way in which the protein production goes haywire in skin cells as they turn cancerous has been studied by researchers at The Rockefeller University.’
Senior author Elaine Fuchs, the Rebecca C. Lancefield Professor and head of the Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, said, "Changes in translation appear to be particularly important as
normal stem cells become malignant, and our new experiments detail the
control mechanisms behind a shift that occurs just prior to the
development of skin cancer," adds Fuchs, who is a Howard Hughes Medical
The research, which identifies a potential
avenue for future cancer treatments, was described in Nature
In order to function, cells need to turn instructions encoded in
their DNA into protein. They do so in two major steps: first, DNA is
transcribed into a molecule called messenger RNA, which is then
translated into protein. Certain cancerous tumors are known to contain
an unusual ratio of protein to messenger RNA, however, which suggests
translation is altered in cancer.
Using mice, the team explored changes in translation that occur as
the animals develop a common type of skin cancer called squamous cell
carcinoma. Adapting a technique developed for cultured cells in
co-author Jonathan Weissman's lab at the University of California, San
Francisco, they captured messenger RNA as it was being translated within
skin stem cells in mice. These molecules were collected from both
normal skin stem cells and those primed to become malignant.
Within the pre-malignant cells, the researchers found decreases in
regular protein production as well as an uptick in tumor-promoting
proteins. Ataman Sendoel, a postdoc in the Fuchs lab and first author on
the study, traced this shift back to a change in the proteins that kick
off the process of translation. In regular skin cells, eIF2 has this
job; in the soon-to-be cancerous cells, he found that eIF2 was
inactivated, and its relative, eIF2A, had taken over.
Next, the researchers looked for evidence that eIF2A has a similar
role in humans. By searching the publicly available Cancer Genome Atlas,
which contains genetic data from 11,000 patients, they found extra
copies of the gene encoding eIF2A in 29% of patients with
squamous cell carcinomas in the lungs, and in 15% of those with
tumors in the head or neck. Moreover, patients in whose cells the gene
was more active had a poorer prognosis, surviving and remaining
disease-free for less time compared to those with normal eIF2A activity.
The team's work suggests eIF2A could potentially provide a
therapeutic target for new cancer treatments, and the researchers have
begun investigating this possibility with help from a grant from the Robertson Therapeutic Development Fund.
"By looking for molecular inhibitors that can turn off eIF2A - and,
as a result the translation of cancer-associated proteins - we suspect it
may be possible to stop the formation of new tumors," says Sendoel.
"For instance, one could envision using such a treatment after tumor
surgery to inhibit any tumor-initiating cells that remain."