Changes in proteins that regulate alternative splicing have been linked to a potent cancer driver gene, according to a multi-institutional consortium of researchers lead by Children’s Hospital of Philadelphia (CHOP). For the study, the researchers used novel computer tools and biological model systems.
Yi Xing, Ph.D., of CHOP, and Owen Witte, MD, of the University of California, Los Angeles (UCLA), collaborated on this study, which was published today in the Proceedings of the National Academy of Sciences.
“Our study provides insight into the relationship between an important cancer driver gene and alternative splicing changes that could be used to guide the development of splicing-targeted cancer therapy,” said Xing, Ph.D., director of the Center for Computational and Genomic Medicine at CHOP and senior author of the study.
Researchers from CHOP, UCLA, and the Roswell Park Comprehensive Cancer Center collaborated on the study. The study’s original authors were John Phillips, MD, Ph.D., a UCLA researcher, and Yang Pan, MS, a visiting scholar at CHOP and UCLA graduate student.
Alternative splicing is a crucial mechanism that allows a single gene to code for a variety of gene products depending on where the RNA is cut, or spliced before it is translated into proteins.
The successful application of PEGASAS to prostate, breast, and lung cancer datasets suggests that this strategy could be useful in analyzing pathway-driven alternative splicing in many cancer types. Given the involvement of oncogenic pathways such as the Myc pathway in pediatric cancers, these tools could reveal pathways and targets for treating pediatric cancers as well.
Yi Xing
This process is frequently exploited by cancer cells to create proteins that promote growth and survival, allowing them to replicate uncontrollably and spread. This occurs in a variety of malignancies, including prostate cancer, which is linked to splicing pattern changes. Scientists, on the other hand, do not fully comprehend the process that leads to this shift.
The team examined RNA sequences from almost 900 prostate tissue samples, ranging from healthy prostate tissue to localized or aggressive metastatic tumor tissue, to better understand the origins and effects of alternative splicing modifications during cancer progression.
The team developed rMATS-turbo, a novel computer program that allows them to examine big datasets quickly. The researchers discovered more than 13,000 alternative splicing events in these 900 prostate samples using this method.
The researchers next created PEGASAS (Pathway Enrichment-Guided Activity Study of Alternative Splicing), an analytic method that they used to uncover probable cancer driver genes and pathways that were linked to these alternative splicing variations.
Myc, a gene involved in normal cell processes that is increased in many malignancies, was connected to alternative splicing modifications in genes that govern alternative splicing, according to the researchers.
Researchers demonstrated that these alternative splicing modifications were definitely caused by Myc by using human prostate cells that were designed to turn on or off Myc activity.
The researchers next used the same PEGASAS technique on datasets from breast cancer and lung cancer and discovered the same link between Myc activity and alternative splicing, implying that Myc activation and consequently splicing disruptions occur in many malignancies.
“The successful application of PEGASAS to prostate, breast, and lung cancer datasets suggests that this strategy could be useful in analyzing pathway-driven alternative splicing in many cancer types,” said Xing. “Given the involvement of oncogenic pathways such as the Myc pathway in pediatric cancers, these tools could reveal pathways and targets for treating pediatric cancers as well.”
The study was supported in part by the Immuno-Oncology Translational Network (IOTN) of the National Cancer Institute’s Cancer Moonshot Initiative (grants U01CA233074, U24CA232979), other National Cancer Institute funding (grants R01CA220238, and P50CA092131), along with funding from the Parker Institute for Cancer Immunotherapy (grant 20163828), the UCLA Tumor Cell Biology Training Grant (T32CA009056), and the Prostate Cancer Research Program under the Office of the Assistant Secretary of Defense for Health Affairs (grant W81XWH-16-1-0216).
