Dr. Yiting Lim named AACR NextGen Star

Overlooked genomic regions may hold cancer-promoting secrets

While only about 2 percent of our DNA codes for proteins, the rest is far from dispensable. Within non-coding DNA regions sit instructions for when and how much genes should be turned on (or off), as well as instructions for making proteins. Lim concentrated her work in an area known as the 5-prime untranslated region, or 5’ UTR, in messenger RNA.

Messenger RNA, or mRNA, is an intermediary between a gene and the protein it encodes. Molecules of mRNA, which carry the code for the amino acid sequence of a protein, serve as instructions for protein-synthesizing molecular machines, which translate this information into a protein. Proteins are essential to every cellular function, from growth to movement.

Though some portion of an mRNA molecule encodes a protein’s amino acid sequence, there are sections, called untranslated regions, or UTRs, that don’t make it into the final product but do carry operating instructions for the protein-building molecules. These molecules “read” the mRNA in a specific direction, starting at what’s termed the 5’ end. This is where the 5’ UTR, the section that Lim studies, sits.

“This whole area of post-transcription regulation, or just the regulation of how proteins are produced, is such a fundamental process, it should be important in disease,” Lim said.

Charting the unknown

Though a few other scientific groups have looked within the 5’ UTR region for mutations that may influence protein production and cancer, they mostly looked at one gene at a time with limited focus on specific diseases, Lim said.

In contrast, she said, “We’re trying to approach it from a broader scale.”

Lim is the first to systematically examine 5’ UTRs in the context of prostate cancer. Her Fred Hutch mentor, physician-scientist Dr. Andrew Hsieh, previously had shown that changes in protein synthesis play a role in the development and progression of the disease, suggesting that areas like 5’ UTR needed a closer look.

“We’re hoping that the landscape of mutations we’ve identified in this region will be a resource for other scientists,” Lim said.

At the time Lim started her work with Sonali Arora, a computational biologist who works with Hsieh’s team, “There was no good technology to study this problem thoroughly,” Hsieh said. So, Lim took on the challenge of filling the technological void.

“We’re not just saying, ‘Look at all these mutations.’ We’re saying, ‘Look at all these mutations, and this is what they do,’” Lim said.

A chance to branch out

When Lim first joined Hsieh’s lab, the project was “completely outside” of her comfort zone, she said.

She’d already seen the different sides of science, having worked in a biotech company outside of Philadelphia as an undergraduate before pursuing a Ph.D. During her graduate work at Johns Hopkins University School of Medicine, using mouse models, Lim studied how a gene network that’s critical during development goes awry in leukemia. As she approached the next phase of her career, Lim was again looking for a new experience.

“I felt like I wanted to branch out,” she said. “It’s important as a postdoc to learn new skills, and I still wanted to be in the realm of cancer biology."

The opportunity to learn more about a fundamental biological process and how it could contribute to cancer development was exactly the right fit. And for an avid hiker like Lim, Seattle’s proximity to the great outdoors was also a strong draw.

“Right from the get-go, Yiting was a star,” Hsieh said. She was only the second postdoc to join his new lab in 2015, and immediately she garnered two separate fellowships, one from the U.S. Department of Defense and the other from AACR. She also impressed Hsieh by climbing Mount Rainier her first year in town. “She’s exceedingly consistent and a very, very thoughtful scientist,” he said.