Researchers reprogram cancer cells

Volume 4, Issue 4, 2015

Summary

Restoring normal miRNA levels in cancer cells can reverse aberrant cell growth.

Panagiotis Z. Anastasiadis, Ph.D.

Panagiotis Z. Anastasiadis, Ph.D.

Researchers in the Mayo Clinic Cancer Center in Florida have discovered a way to potentially reprogram cancer cells back to the normal cells they once were.

Their findings, published in September 2015 in the journal Nature Cell Biology, represent "an unexpected new biology that provides the code and the software for turning off cancer," said Panagiotis Z. Anastasiadis, Ph.D., the study's senior investigator and chair of the Department of Cancer Biology within the Mayo Clinic Cancer Center in Florida.

That code was revealed 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.

Researchers 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.

In laboratory experiments, researchers showed that restoring the normal miRNA levels in cancer cells can reverse aberrant cell growth.

"Our 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," said the published study's lead author, Antonis Kourtidis, Ph.D., a research associate in the Mayo Clinic Cancer Center in Florida. "Most significantly, it uncovers a new strategy for cancer therapy."

That problem arose from conflicting reports about E-cadherin and p120 catenin — adhesion proteins that are essential for normal epithelial tissues to form, 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 explained. "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."

Dr. Anastasiadis' theory turned out to be true, but what was regulating this behavior was still unknown.

To answer this question, he and his colleagues 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 said.

"We believe that loss of the apical PLEKHA7-microprocessor complex is an early and somewhat universal event in cancer," Dr. Anastasiadis said. "In the vast majority of human tumor samples we examined, this apical structure is absent, although E-cadherin and p120 are still present. This produces the equivalent of a speeding car that has a lot of gas (the bad p120) and no brakes (the PLEKHA7-microprocessor complex).

"By administering the affected miRNAs in cancer cells to restore their normal levels, we should be able to re-establish the brakes and restore normal cell function," Dr. Anastasiadis said. "Initial experiments in some aggressive types of cancer are indeed very promising."