Yanhong Shi, Ph.D. (left), with Qi Cui, a graduate student at City of Hope’s Irell & Manella Graduate School of Biological Sciences
An important role of stem cells in adults is to repair and replace certain worn out tissue, helping the body to remain healthy. Unfortunately, cancer also has stem cells that aid in keeping tumors in top shape.
Now, Yanhong Shi, Ph.D., professor and director of the Division of Stem Cell Biology Research at Beckman Research Institute of City of Hope, believes she and colleagues have found a way to suppress the growth and self-renewal in a certain type of cancer stem cell.
Glioblastoma stem cells, or GSCs, contribute to the initiation and development of the brain tumor of the same name, known for its aggressive and deadly nature. While glioblastoma tumors are rare, the tumor cells grow and spread quickly, have a nearly 100 percent recurrence rate, and are very difficult to treat due to their location deep in the brain.
But a new target found by the team of researchers led by Shi and Qi Cui, a graduate student at City of Hope’s Irell & Manella Graduate School of Biological Sciences, could lead to a successful therapeutic option for this often lethal cancer.
The City of Hope scientists, along with collaborators from the University of Chicago and the Shanghai Institute of Materia Medica, published results of their study, “m6A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells,” in the March 14 issue of the prestigious peer-reviewed journal Cell Reports.
“We found that m6A RNA methylation regulates tumor production through targeting cancer stem cells — the tumor initiating and propagating cells — and that a small molecule inhibitor of the fat-mass and obesity-associated gene called FTO suppresses glioblastoma progression and prolongs the lifespan of tumor-bearing animals, presumably by maintaining the m6A methylation modification” said Shi. “Our work indicates that m6A modification plays a critical role in regulating glioblastoma stem cells that novel cancer therapies should consider and aim to target.”
In general, RNA modifications play critical roles in important biological processes, but the specific functions of m6A in cancer biology and cancer stem cells remain largely unknown. In fact, although m6A is most abundant in the brain, no study on the role of m6A modification in either brain development or brain disorders has been previously reported — save for one showing a role in the neural function of fly models — making Shi’s study the first of its kind.
The role of m6A in cancer is only starting to be revealed and this study provides a causal link between mRNA m6A methylation and glioblastoma tumor development, which represents an important step toward developing therapeutic strategies to treat glioblastoma and potentially other cancers.
“The next step in this line of research is to develop more potent FTO inhibitors to target cancer stem cells in the hopes of better suppressing tumor progression and prolonging lifespans, and to determine the mechanisms underlying how m6A RNA methylation regulates the formation of tumors,” said Shi. “This work and other studies demonstrate important roles for m6A in regulating multiple types of cancers, such as glioblastoma and leukemia, suggesting that targeting m6A modification machinery can be a general therapeutic tool for a variety of cancers.”
Additional City of Hope scientists who helped make this work possible include Peng Ye, M.D., Li Li, M.S., Qiuhao Qu, Ph.D., and Guoqiang Sun, Ph.D., from the Shi lab of Beckman Research Institute of City of Hope, and Guihua Sun, Ph.D., and Arthur Riggs, Ph.D., the Samuel Rahbar Chair in Diabetes & Drug Discovery, from the Diabetes & Metabolism Research Institute at City of Hope.