Researchers reveal how to reprogram cancer cells into normal cells

By John Murphy, MDLinx
Published January 13, 2016

Key Takeaways

Researchers have uncovered a mechanism that permits normal cells to become tumorigenic. Not only that, but they have also discovered a way to reprogram tumor cells to turn back into normal cells, according to a report in published online August 24, 2015 in Nature Cell Biology.

“It’s going to change the way we think about cancer progression,” said the study’s senior investigator, Panos Anastasiadis, PhD, chair of the Department of Cancer Biology at Mayo Clinic’s campus in Jacksonville, FL.

The first clue in the discovery had to do with adhesion molecules, the “glue” that holds cells together, Dr. Anastasiadis explained. But it became evident to researchers that in addition to this helpful role, adhesion molecules also played a destructive role in driving tumorigenesis. Dr. Anastasiadis and his colleagues wanted to know why adhesion molecules were sometimes helpful and also sometimes harmful.

They found that when these molecules form adhesions, they signal through microRNAs (miRNAs), which regulate the program that drives cell growth. “In normal cells, the adhesion molecules regulate microRNAs and inhibit cell growth,” Dr. Anastasiadis said. “What we found is that in cancer cells, the microRNAs are not regulated anymore, and as a result the cancer cells grow uncontrollably.”

The second clue in the discovery was finding what “microprocessor” regulated whether adhesion molecules played the good role (stopping growth) or the bad role (fostering growth). So, the researchers studied a new protein called PLEKHA7, which associates with adhesion molecules E-cadherin and p120 only at the top—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.”

The researchers found additional evidence of this in human tumors, where the regulatory microprocessor was missing in most samples. “In the vast majority of human tumor samples we examined, this apical structure was absent, although E-cadherin and p120 were still present,” Dr. Anastasiadis said. He compared this growth to a speeding car that has a lot of gas (the bad p120) but no brakes (the PLEKHA7-microprocessor complex).

Most importantly, the researchers performed laboratory experiments that turned this process around, restoring the normal miRNA levels in cancer cells and reversing aberrant cell growth. “By regulating these microRNAs that are deregulated and by getting them back into the cancer cells, we can effectively reprogram them to become and behave as normal,” Dr. Anastasiadis said. “So we can take very aggressive tumor cells that are growing and migrating, replenish them with the microRNAs that are deregulated, and that effectively turns them into normal cells.”

The challenge now is to find delivery methods to do so, he added.

Furthermore, this discovery will also aid diagnosis, the researchers predicted. Deregulation of adhesion signaling is going to be consistent with cancer in premalignant lesions. “So we believe that we will have a diagnostic [technique] that very easily can tell you if a biopsy is actually a cancerous lesion or not,” Dr. Anastasiadis said.

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