shinyDepMap, a tool to identify targetable cancer genes and their functional connections from Cancer Dependency Map data
Abstract
Individual cancers rely on distinct essential genes for their survival. The Cancer Dependency Map (DepMap) is an ongoing project to uncover these gene dependencies in hundreds of cancer cell lines. To make this drug discovery resource more accessible to the scientific community we built an easy-to-use browser, shinyDepMap (https://labsyspharm.shinyapps.io/depmap). shinyDepMap combines CRISPR and shRNA data to determine, for each gene, the growth reduction caused by knockout/knockdown and the selectivity of this effect across cell lines. The tool also clusters genes with similar dependencies, revealing functional relationships. shinyDepMap can be used to 1) predict the efficacy and selectivity of drugs targeting particular genes; 2) identify maximally sensitive cell lines for testing a drug; 3) target hop, i.e., navigate from an undruggable protein with the desired selectivity profile, such as an activated oncogene, to more druggable targets with a similar profile; and 4) identify novel pathways driving cancer cell growth and survival.
Data availability
Data files have been provided for Figures 1, 3, 4, and 5 on FigShare: https://figshare.com/projects/shinyDepMap_Source_Data/97382 (DOIs: 10.6084/m9.figshare.13653251.v1, 10.6084/m9.figshare.13653257.v1, 10.6084/m9.figshare.13653260.v1, 10.6084/m9.figshare.13653266.v1, 10.6084/m9.figshare.13653272.v1, 10.6084/m9.figshare.13653278.v1, 10.6084/m9.figshare.13653281.v2)
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shinyDepMap - Source Data 1FigShare, doi:10.6084/m9.figshare.13653251.
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shinyDepMap - Source Data 2FigShare, doi:10.6084/m9.figshare.13653257.v1.
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shinyDepMap - Source Data 3FigShare, doi:10.6084/m9.figshare.13653260.v1.
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shinyDepMap - Source Data 4FigShare, doi:10.6084/m9.figshare.13653266.v1.
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shinyDepMap - Source Data 5FigShare, doi:10.6084/m9.figshare.13653272.v1.
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shinyDepMap - Source Data 6FigShare, doi:10.6084/m9.figshare.13653278.v1.
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shinyDepMap - Source Data 7FigShare, doi:10.6084/m9.figshare.13653281.v2.
Article and author information
Author details
Funding
Japan Society for the Promotion of Science (H29-814)
- Kenichi Shimada
National Institute of General Medical Sciences (R35GM131753)
- Timothy J Mitchison
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Erica A Golemis, Fox Chase Cancer Center, United States
Version history
- Received: March 20, 2020
- Accepted: February 6, 2021
- Accepted Manuscript published: February 8, 2021 (version 1)
- Accepted Manuscript updated: February 10, 2021 (version 2)
- Version of Record published: March 2, 2021 (version 3)
Copyright
© 2021, Shimada et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The role of processing bodies (P-bodies) in tumorigenesis and tumor progression is not well understood. Here, we showed that the oncogenes YAP/TAZ promote P-body formation in a series of cancer cell lines. Mechanistically, both transcriptional activation of the P-body-related genes SAMD4A, AJUBA, and WTIP and transcriptional suppression of the tumor suppressor gene PNRC1 are involved in enhancing the effects of YAP/TAZ on P-body formation in colorectal cancer (CRC) cells. By reexpression of PNRC1 or knockdown of P-body core genes (DDX6, DCP1A, and LSM14A), we determined that disruption of P-bodies attenuates cell proliferation, cell migration, and tumor growth induced by overexpression of YAP5SA in CRC. Analysis of a pancancer CRISPR screen database (DepMap) revealed co-dependencies between YAP/TEAD and the P-body core genes and correlations between the mRNA levels of SAMD4A, AJUBA, WTIP, PNRC1, and YAP target genes. Our study suggests that the P-body is a new downstream effector of YAP/TAZ, which implies that reexpression of PNRC1 or disruption of P-bodies is a potential therapeutic strategy for tumors with active YAP.