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The updated application, NetBID2, successfully uncovers difficult-to-identify proteins that drive biological processes (such as rapid cell growth) contributing to cancer. These hidden drivers present new therapeutic opportunities, either because existing drugs can already target them or because they might inspire drug developers to make new therapeutics.
“We made it easier to find hidden drivers,” said corresponding author Jiyang Yu, Ph.D., St. Jude Department of Computational Biology. “Finding hidden drivers is important because many of these are potentially druggable targets. NetBID2 can find these drivers and potentially move them quickly into clinical trials. We may be able to re-purpose an already FDA-approved drug that targets an identified hidden driver to a completely different patient population that may benefit.”
A network approach to finding hidden drivers
Large sets of RNA sequencing data from specific cells or cancer types can contain valuable information necessary to find hidden drivers of disease; however, standard analysis tools struggle to find them. NetBID2 is a sequel to the original tool developed by Yu in 2018. He specifically designed these tools to find hidden drivers by squeezing out more from “big data.”
“NetBID2 enables us to maximize the data we have,” said Yu, “particularly RNA sequencing data. It goes beyond the traditional mutation or differential gene expression data to expose hidden events and information that may be functionally important.”
Hidden drivers cannot be discovered by conventional genomics or sequencing approaches because their activity depends on post-translational modifications and other mechanisms that are invisible to traditional sequencing but affect the expression of other genes.
Therefore, NetBID2 takes RNA sequencing data, then generates a gene-gene interactome. This interactome tracks the relationships between driver candidates and their downstream effector genes to determine which signaling proteins are most central to the key relationships that fuel disease. These “central hubs” directing the network are the hidden drivers.
“NetBID2 looks for a hidden driver like the FBI would look for a crime boss,” Yu said. “If you look at the suspect, there’s no direct evidence to connect them with any crime. The way to capture them is first to build a network of associates. We do the same when we build the biological network by collecting a lot of data on its members and their relationships. Then we look for the boss’s first neighbors in the network when we look at a hidden driver’s activity. That’s the only way to capture the boss — by inference from their activities — otherwise, there is no way to identify them. We find these hidden drivers’ guilt by association.”
As proof of the tool’s capabilities, the St. Jude group showed it could find biologically meaningful hidden drivers in three unrelated samples. Using NetBID2, the team found unappreciated roles for MYC in adult lung cancer and for NOTCH1 in difficult-to-treat pediatric leukemia that standard differential expression analysis at the mRNA or protein levels hadn’t uncovered, despite the genes’ having been previously linked to cancer. They also found an unappreciated role for Gabpa in normal immune cell function. The gene’s importance was context-specific in each case, highlighting the need for targeted analyses.
The software’s other capabilities, such as new visualization tools, are meant to facilitate further analysis and discovery of hidden drivers from complex networks of RNA-seq and, in some cases, proteomics data.
NetBID2 is freely available on a GitHub repository. The St. Jude Cloud, which includes a NetBID2 app and data from many multi-omics projects, is also freely available for other scientists to use for further discovery of hidden drivers of basic biology and disease.
Authors and funding
The study’s first author is Xinran Dong, formerly of St. Jude. The other authors are Liang Ding, Andrew Thrasher, Xinge Wang (formerly), Jingjing Liu, Qingfei Pan, Jordan Rash, Yogesh Dhungana, Xu Yang, Isabel Risch (formerly), Yuxin Li (formerly), Lei Yan, Michael Rusch, Clay McLeod, Koon-Kiu Yan, Junmin Peng, Hongbo Chi and Jinghui Zhang, all of St. Jude.
The study was supported by grants from the National Institutes of Health (R01GM134382, U01CA264610 and P30CA021765-403 41S3) and ALSAC, the fundraising and awareness organization of St. Jude.
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St. Jude Children’s Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress blog, and follow St. Jude on social media at @stjuderesearch.
