Alternative Splicing Identified as a Potential Driver of Aggressive Cancers

Illustration of a cancer cell

Researchers from Children’s Hospital of Philadelphia (CHOP) have led a multi-institutional group to study the link between a strong cancer driver gene that impacts changes in proteins related to alternative splicing regulation. The scientists developed new computational tools and biological model systems for the study, led by Yi Xing, Ph.D., at CHOP and Owen Witte, M.D., at the University of California, Los Angeles (UCLA).

Alternative splicing is the process in which exons and introns are separated in a pre-mRNA strand, and various combinations of exons in the mRNA can be used to translate into proteins. Through this mechanism, a single gene can code for multiple (usually closely related) proteins.

Alternative splicing is an essential process, and it is the RNA that is cut, or spliced, before being translated into proteins, meaning regulation happens at the transcription level. Cancer cells often take advantage of this process to produce proteins that promote growth and survival, allowing them to replicate uncontrollably and metastasize. This happens in many cancers, including prostate cancer, which is associated with shifts in splicing patterns. Yet scientists do not fully understand the process that leads to this change.

“Our study provides insight into the relationship between an important cancer driver genes and alternative splicing changes that could be used to guide the development of splicing-targeted cancer therapy,” said Xing, director of the Center for Computational and Genomic Medicine at CHOP and senior author of the study.

To better understand the causes and consequences of alternative splicing changes during cancer progression, the team examined RNA sequences from nearly 900 prostate tissue samples, ranging from healthy prostate tissue to localized or aggressive metastatic tumor tissue. To efficiently analyze such a large sequencing dataset, the team created a computational program called rMATS-turbo. This program allowed the researchers to identify more than 13,000 alternative splicing events that occurred across these 900 prostate samples.

The collaborative effort involved researchers at CHOP, UCLA, and the Roswell Park Comprehensive Cancer Center. John Phillips, M.D., Ph.D., a researcher at UCLA, and Yang Pan, a visiting scholar at CHOP and graduate student at UCLA, were first authors of the study.

After the team identified alternative splicing events and rate of occurrence, they developed an analytic tool, dubbed PEGASAS (Pathway Enrichment-Guided Activity Study of Alternative Splicing), to identify which splicing patterns led to the creation of proteins that may help drive cancer genes and pathways.  They were searching for alternative splicing patterns that correlated to cancer development.

The scientists found that Myc, a gene normally involved in cell functions but amplified in many cancers, was linked to alternative splicing changes in genes that themselves regulate alternative splicing. Using human prostate cells that were engineered to turn on or off Myc activity, researchers further confirmed that these alternative splicing changes were indeed driven by Myc.

The team of researchers then applied the same PEGASAS strategy to breast cancer and lung cancer datasets and found the same association between Myc activity and alternative splicing, suggesting Myc activation – and thus disruptions in splicing – occur in many cancer types.

Of course, the MYC family of oncogenes is known to be deregulated in over half of all known human cancers, and this deregulation is frequently associated with poor prognosis and unfavorable patient survival.  Myc has a central role in almost every aspect of the oncogenic process, orchestrating proliferation, apoptosis, differentiation, and metabolism,meaning that it may be possible that alternative splicing is just one downstream effect this gene has during the cancer development process.

“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.”

While this research is in its early stages, linking protein changes to cancer development is an important step in understanding cancer development.  If individual spicing patterns for particular proteins can be identified as cancer causing, it would open the door for precision medicine to step in and block those particular proteins from being translated.

It would be of great interest to see if alternative splicing was involved in cancer types that did not involve Myc, and if alternative splicing could be linked to cancers that involved different genetic mutation pathways.

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