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Cells need normal, non-mutated Genes to
Newswise — Corrupt lifestyles and vices go
hand in hand; each feeds the other. But even
the worst miscreant needs customary societal
amenities to get by.
It’s the same with cancer cells. While they
rely on vices in the form of genetic
mutations to wreak havoc, they must sustain
their activity, and that requires equal
parts vice and virtue.
According to a new study in the May 29 issue
of Cell, cancer cells rely heavily on many
normal proteins to deal with stress and
maintain their deviant state.
Researchers at Harvard Medical School and
Brigham and Women’s Hospital used a
technique called RNA interference (RNAi) to
dial down the production of thousands of
proteins and determine which were required
for cancer cell survival.
“Cancer cells actually leverage many genes
that don’t harbor mutations to maintain
their malignant lifestyles,” says first
author and postdoctoral researcher Ji Luo.
“These genes probably help them deal with
the problems that develop as a result of the
inappropriate presence of growth and
survival signaling in tumor cells.”
Being a cancer cell isn’t easy.
Think of all the DNA replication and protein
production involved, not to mention the
abnormal architecture of a tumor, which
deprives cells of oxygen.
Survival requires a complete kit of stress
“Researchers often characterize cancer cells
as oncogene addicts, but they’re just as
reliant on normal genes that alleviate
stress,” explains senior author Stephen
Elledge, a professor at HMS and Brigham and
“These stress management genes deserve
attention as potential therapeutic targets.”
In recent years, the National Cancer
Institute has supported an ambitious effort
to understand the molecular basis of cancer
by sequencing cancer genomes.
Elledge and Luo note that this Cancer Genome
Atlas project would miss the stress
“If these genes are intact, they won’t stand
out when you compare the DNA sequences of
cancer cells with normal cells,” says Luo.
So the team took a different approach to
test their “non-oncogene addiction”
acquired two human cell lines, identical in
every way except for one—the presence or
absence of a Ras oncogene.
Ras mutations are prevalent in many deadly
cancers, and researchers have not been
successful in developing drugs against the
The team used molecules called shRNAs to
interfere with the production of thousands
of normal, healthy proteins in the two cell
gave the cells time to divide and sifted
through the data to determine which proteins
were required for survival.
(In the past, labs relied on large robots to
complete these types of screens, but Elledge
and others have refined the technology in an
effort to make RNAi affordable and
conducted his genome-wide screen in test
tubes without the aid of a robot.)
Despite their similarities, the two cell
lines responded differently to a number of
That is, normal cells tolerated low levels
of a particular protein while cells with the
Ras mutation perished. Luo validated 50 of
these hits in a second pair of cell lines.
Dozens of these represent brand new
“This opens the door to using a drug
cocktail approach to treat tumors driven by
Ras mutations,” says Elledge, who is also an
investigator with Howard Hughes Medical
“We might be able to tinker with the levels
of these proteins and cripple cancer cells
without hurting normal cells in the body,
though this needs to be tested in tumor
“This type of functional approach
complements the physical mapping of cancer
genomes, but provides a much more direct
path to new anti-cancer drug targets,” adds
“The genes that are critical for maintaining
the malignant state will really crystallize
when we combine forces.”
This research is supported by funding from
the AACR Prevent Cancer Foundation
AstraZeneca Fellowship in Translational Lung
Cancer Research, the Damon Runyon Cancer
Research Foundation, the National Institutes
of Health, the Department of Defense, and
the Susan G. Komen for the Cure Foundation.