February 11, 2019

The director's cut: Heidi Dvinge looks at RNA splicing with a film critic's eye

Madison, Wis. — After filming a movie, scenes are cut and rearranged to tell the director’s story. A similar editorial process occurs in our cells in a process called RNA splicing. Before the DNA code is translated into a protein, it must first be converted into RNA, its single-stranded mirror image. The resulting strand of RNA is spliced to generate an edited strand that is used to code for new proteins.

RNA splicing allows cells that contain the same genetic information to code for different proteins and to complete different functions.

“You can imagine, depending on what scenes you use or add into a movie, you get a slightly different meaning out of it. Splicing is a way for one gene in our cell to have these slightly different meanings,” Heidi Dvinge, PhD, assistant professor in the Department of Biomolecular Chemistry, said. Dvinge joined the UW Carbone Cancer Center in 2017 and studies the mechanisms and consequences of RNA splicing and how errors in splicing can give rise to cancers.

Splicing is a normal function in healthy cells. However, sometimes splicing can go wrong, and portions of the RNA are rearranged or removed in a way that will negatively affect protein structure and function. Researchers have only recently found that these rogue edits can be involved with cancer and other diseases.

“In some cases, if you take out a scene, suddenly the whole movie doesn’t make sense. Imagine Titanic where the ship never hits the iceberg. Then for the rest of the movie, all these people running around jumping into the water and it doesn’t make any sense whatsoever,” Dvinge said. “That’s what happens when things go wrong with splicing. In the last 5-6 years, people have really started to realize how changes in splicing can act as a disease driver.”

One area of research Dvinge is currently pursuing is to investigate the role of RNA splicing in the development of breast cancer. A protein called the estrogen receptor (ER) regulates cell growth in healthy cells, but changes in ER function have been implicated in breast cancer. Dvinge thinks splicing errors in the RNA that code for ER might be one cause for this abnormal activity.

“The estrogen receptor protein usually responds to the presence of estrogen in the body. That’s part of normal development,” Dvinge said. “But when we look at ERs in breast cancer patients, we often find that ‘scenes’ that are otherwise recognized by the drugs used to treat some patients are suddenly absent. The abnormal ER may no longer recognize estrogen or drugs,” potentially resulting in unregulated cell growth.

Through her research, Dvinge hopes to better understand the underlying causes and consequences of splicing mis-regulation in breast cancer. Though using these insights to design new drugs and treatments is still far off, Dvinge envisions practical applications even in the early stages of her research.

“If we find out ER mis-splicing causes resistance to particular drugs in breast cancer treatment, we can potentially use that as a biomarker in circulating tumor cells or test for it in the tumor,” Dvinge said. ”If these ER splicing variants are present, we could say that this patient is likely to not respond to this treatment, so let’s treat them in a different way.”

Dvinge also thinks that understanding how RNA mis-splicing affects ER function and breast cancer could lead to insights in other cancers that have been linked to ER and other hormone receptor proteins.

“What about the ER in ovarian cancer? What about the ER in uterine cancer? There are other hormone-regulated proteins called the androgen receptor and progesterone receptor implicated in prostate, breast and other cancers,” said Dvinge. “Rather than taking a narrow approach to focus on what this one molecule is doing in this one disease, I think we can find some commonalities across these different diseases to use what we learn from the role of ER splicing variants in breast cancer and directly translate that into other diseases.”