Researchers at Fred Hutch Cancer Center have identified a previously overlooked molecular regulator that helps determine whether prostate tumors remain sensitive to treatment or evolve into a more aggressive, drug-resistant form of the disease.
The findings, published Oct. 7 in Nature , reveal for the first time that a single transfer RNA, or tRNA, can control the identity of prostate cancer cells and influence their response to therapy.
"The discovery opens an entirely new realm of cancer biology that was previously unrecognized," said co-corresponding author Andrew Hsieh, MD , a professor and associate director of Fred Hutch's Human Biology Division. "Historically, tRNAs have been thought to play a bystander role in cell maintenance and disease, but our study shows that tRNAs can actively shape the identity of cancer cells."
Prostate cancer, a leading cause of cancer in men , can shift cellular characteristics over time. Initially, prostate cancer depends on the activity of the androgen receptor, a protein that fuels tumor growth and is the primary target of standard therapies. But then many tumors shift to an androgen receptor-independent state. Once independent of the androgen receptor, prostate cancer tumors become more aggressive and less responsive to therapy.
First author of the Nature paper, Yeon Soo Kim, PhD, a Fred Hutch postdoctoral researcher in Hsieh's lab, sought to understand the molecular players underlying how prostate cancer changes its identity and becomes resistant to treatment. Kim received a National Cancer Institute K99/R00 Pathway to Independence Award to support the studies.
"We already knew that genomic mutations or transcriptional factor-dependent genetic expression are altered during the cancer progression and can lead to the development of treatment resistance," Kim explained. "But we wanted to know more about how mRNA translation — also known as protein synthesis — is involved when the disease becomes more aggressive."
Kim examined one of the steps in mRNA translation: when tRNA takes biological information from mRNA in order to deliver amino acids that combine to build proteins.
Kim used prostate cancer cell lines, mouse models and tumor samples from patients to examine the role of tRNA in the transition to the aggressive form of prostate cancer.
Across all model systems, Kim and her coauthors observed a consistent pattern: a specific tRNA called tRNA1Arg(UCU) was high in androgen receptor-dependent prostate cancer cells but diminished in less androgen receptor-dependent, treatment-resistant tumors.
Then, Kim did additional experiments and found that treatment-resistant tumors, when given the specific tRNA, could go back to being sensitive to treatments targeting the androgen receptor.
"We found that we can shift the cell state between androgen receptor-dependent to an androgen receptor-independent state with a single tRNA," Kim said. "This is important because changes in cell identity are a major reason prostate cancers become resistant to treatment. We found that this tRNA can influence whether cells remain in a drug-sensitive state or transition to one that is more aggressive."
The findings could be applied to other diseases, too.
"In this study we used prostate cancer as an archetype to study tRNA dependent state changes, but we think it's just the beginning," said Kim, who is planning to pursue such studies when she establishes her own lab. "We can apply this approach to any type of disease models or other types of cancers that undergo identity switches after treatment, such as lung and breast cancers."
Kim and Hsieh are also looking into how tRNA could be used as a biomarker or therapeutic target for aggressive prostate cancer, which could help guide more precise treatments or new treatments for patients.
Hsieh holds the Larry and Virginia Gordon Endowed Chair in Prostate and Bladder Cancer Research at Fred Hutch. He is also a professor in the Division of Hematology and Oncology at the University of Washington School of Medicine.
Co-corresponding author Tao Pan, PhD, is at the University of Chicago. The study was funded by multiple grants from the National Institutes of Health, including the Pacific Northwest Prostate Cancer SPORE , and the U.S. Department of Defense. Additional funding was from the Prostate Cancer Foundation and the American Cancer Society.
