August 24, 2015) Cancer
researchers dream of the day they can force tumor cells to morph back to the
normal cells they once were. Now, researchers on Mayo Clinic’s Florida campus
have discovered a way to potentially reprogram cancer cells back to normalcy.
The finding, published in Nature Cell Biology, represents
“an unexpected new biology that provides the code, the software for turning off
cancer,” says the study’s senior investigator, Panos Anastasiadis, Ph.D., chair
of the Department of Cancer Biology on Mayo Clinic’s Florida campus.
That code was unraveled by the discovery that adhesion
proteins — the glue that keeps cells together — interact with the
microprocessor, a key player in the production of molecules called microRNAs
(miRNAs). The miRNAs orchestrate whole cellular programs by simultaneously
regulating expression of a group of genes. The investigators found that when
normal cells come in contact with each other, a specific subset of miRNAs
suppresses genes that promote cell growth. However, when adhesion is disrupted
in cancer cells, these miRNAs are misregulated and cells grow out of control.
The investigators showed, in laboratory experiments, that restoring the normal
miRNA levels in cancer cells can reverse that aberrant cell growth.
Lead authors Panos
Anastasiadis, Ph.D., and Antonis Kourtidis, Ph.D.
“The study brings together two so-far unrelated research
fields — cell-to-cell adhesion and miRNA biology — to resolve a long-standing
problem about the role of adhesion proteins in cell behavior that was baffling
scientists,” says the study’s lead author Antonis Kourtidis, Ph.D., a research
associate in Dr. Anastasiadis’ lab. “Most significantly, it uncovers a new
strategy for cancer therapy,” he adds.
That problem arose from conflicting reports about E-cadherin
and p120 catenin — adhesion proteins that are essential for normal epithelial
tissues to form, and which have long been considered to be tumor suppressors.
“However, we and other researchers had found that this hypothesis didn’t seem
to be true, since both E-cadherin and p120 are still present in tumor cells and
required for their progression,” Dr. Anastasiadis says. “That led us to believe
that these molecules have two faces — a good one, maintaining the normal
behavior of the cells, and a bad one that drives tumorigenesis.”
Researchers on
Mayo Clinic’s Florida campus have discovered a way
to potentially
reprogram cancer cells back to normalcy.
Their theory turned out to be true, but what was regulating
this behavior was still unknown. To answer this, the researchers studied a new
protein called PLEKHA7, which associates with E-cadherin and p120 only at the
top, or the “apical” part of normal polarized epithelial cells. The
investigators discovered that PLEKHA7 maintains the normal state of the cells,
via a set of miRNAs, by tethering the microprocessor to E-cadherin and p120. In
this state, E-cadherin and p120 exert their good tumor suppressor sides.
However, “when this apical adhesion complex was disrupted
after loss of PLEKHA7, this set of miRNAs was misregulated, and the E-cadherin
and p120 switched sides to become oncogenic,” Dr. Anastasiadis says.