Monday, July 13, 2015
MicroRNAs are small molecules that regulate gene function. The laboratory of cancer biologist Andrea Ventura has found that one microRNA, miR-19, plays an important role in tumor cell growth in B cell lymphoma and prostate cancer. Blocking miR-19 seems to make cells resistant to these cancers while having no ill effects. The researchers also clarified the function of related microRNAs, which appear to play essential roles in embryonic development.
- MicroRNAs are small molecules that regulate gene function.
- Targeting specific microRNAs shows promise as a cancer therapy.
- Blocking miR-19 made animals resistant to two cancers.
- Researchers also shed light on the role of related microRNAs.
As researchers gain a clearer understanding of how genes regulate cellular functions, they are discovering new ways to manipulate them for therapeutic use. One emerging approach involves using small molecules called microRNAs.
Discovered in the early 1990s, microRNAs have been found to play an essential role in gene regulation. In cells, genes are expressed when DNA is transcribed into messenger RNA molecules, which in turn are translated into proteins. However, microRNAs — noncoding fragments of RNA — can bind to messenger RNAs, interfering with this final step. Through this simple process, a single microRNA can modify the expression of hundreds of genes.
For the past six years, Memorial Sloan Kettering cancer biologist Andrea Ventura and collaborators in his laboratory have been studying microRNA activity, seeking to understand how it may contribute to or suppress cancer. In 2009, his Sloan Kettering Institute laboratory reported that one particular microRNA, miR-19, plays an important role in promoting tumor cell growth.
The researchers theorized that finding ways to block miR-19 with a drug could potentially prevent some cancers, but it was not clear whether simply obstructing this one microRNA would be sufficient, since cancers frequently manage to evade therapeutic roadblocks. In addition, it was possible that miR-19 is essential for cells to function normally and that targeting it would cause serious toxicity.
Targeting miR-19 to Block Cancer
Now, in a recent study, Dr. Ventura’s laboratory has shown that two types of cancer — B cell lymphoma and prostate cancer — depend on miR-19 in order to thrive. In mouse experiments, the researchers showed that removing miR-19 made the animals strikingly resistant to these cancers. Perhaps more importantly, the mice lacking miR-19 otherwise seemed largely normal, suggesting that drugs targeting it would carry little or no serious side effects.
“If mice without miR-19 are mostly fine, we could find a way to target miR-19 with significant anticancer effects with very little or no toxicity,” says Ping Mu, one of the study’s first authors. (Dr. Mu was a graduate student in Dr. Ventura’s lab and now is a postdoctoral fellow in the laboratory of MSK physician-scientist Charles Sawyers.) “The therapeutic window would be very wide — we could possibly give large doses with low risk. But this finding is also an important proof that certain tumors need miR-19 to grow optimally.”
Dr. Ventura explains that although designing drugs to target a microRNA such as miR-19 is relatively simple, delivering them to the cancer cells has proved difficult. But he says researchers have recently developed better delivery techniques, and he hopes it will soon be possible to test the effectiveness of the miR-19 targeted approach.Back to top
Assembling the Pieces through a Team Effort
The finding resulted from an extended collaborative effort among members of Dr. Ventura’s laboratory, in particular Dr. Mu and fellow postdoctoral fellows and co-first authors Yoon-Chi Han and Joana Vidigal. Six years ago, the team began focusing on a group of microRNAs — called a microRNA cluster — because of its suspected role in cancer. This cluster, known as miR-17~92, is often overexpressed in cancer cells and contains miR-19 and five other microRNAs. After six years of work, the researchers have finally been able to tease out the role of each individual microRNA within the cluster.
“We can’t do an experiment where we remove the entire cluster because the mouse dies,” Dr. Ventura says. “But we can remove individual microRNAs and ask what their contribution is.”
In the new study, reported in Nature Genetics, the researchers sought to find out how essential miR-19 was in the development of cancer. They used genetically modified mouse models of either B cell lymphoma or prostate cancer. When these mice were bred with mice in which miR-19 had been removed, their offspring proved to be very resistant to the cancers but otherwise seemed fine.
Dr. Han’s hypothesis is that miR-19 may have a normal purpose of helping the body respond to stress by enabling certain types of cells, such as lymphocytes, to proliferate rapidly for a brief period in response to disease or injury. “This would explain why humans and other animals have miR-19 in the first place, and it would link its role in cancer to its physiologic function — both characterized by rapid cell growth,” she says.Back to top
New Light on a Human Developmental Syndrome
Beyond miR-19, the researchers were also able to clarify the roles of the other microRNAs in the cluster.
“When we did these experiments, we found that while miR-19 seems to be the important microRNA in cancer, other members of the cluster play essential roles in embryonic development,” Dr. Ventura says.
One aspect of this is new insight into an inherited disease known as Feingold syndrome. People with this affliction have a variety of skeletal defects and various degrees of learning disabilities. Back in 2011, the Ventura lab, in collaboration with researchers in Paris, reported that some patients affected by this disease are missing one copy of the gene in the miR-17~92 cluster.
“At the time it wasn’t possible to know which microRNAs within the cluster were responsible for the developmental defects,” Dr. Vidigal says. “But thanks to this new study we have now identified the culprits — altered forms of miR-17 and miR-20 — and we can design experiments to understand how they do it.”
“The novelty of the work that Yoon-Chi, Ping, and Joana have done is twofold,” Dr. Ventura says. “In addition to the obvious cancer relevance, this is the first time that someone has been able to dissect an entire microRNA cluster and see how the different components work together. As such, it might have broad implications for the microRNA field in general.”
Dr. Ventura pointed out the importance of collaboration and commitment to exploring a particular scientific question, fostered by the strong support that exists at MSK. “No single postdoc would have been able to do this — it involved so many experiments, so many mouse strains. Bringing together people with different areas of expertise probably would not have been possible anywhere else.”Back to top