1. Cancer Biology
  2. Computational and Systems Biology

shinyDepMap, a tool to identify targetable cancer genes and their functional connections from Cancer Dependency Map data

  1. Kenichi Shimada  Is a corresponding author
  2. John A Bachman
  3. Jeremy L Muhlich
  4. Timothy J Mitchison
  1. Harvard Medical School, United States
https://doi.org/10.7554/eLife.57116
Share this article
Cite this article
  1. Kenichi Shimada
  2. John A Bachman
  3. Jeremy L Muhlich
  4. Timothy J Mitchison
(2021)
shinyDepMap, a tool to identify targetable cancer genes and their functional connections from Cancer Dependency Map data
eLife 10:e57116.
https://doi.org/10.7554/eLife.57116
  2. Download BibTeX
  3. Download .RIS

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)

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Kenichi Shimada

    Department of Systems Biology and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, United States
    For correspondence
    kenichi_shimada@hms.harvard.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8540-9785

  2. John A Bachman

    Department of Systems Biology and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, United States
    Competing interests
    John A Bachman, has received consulting fees from Two Six Labs, LLC.

  3. Jeremy L Muhlich

    Laboratory of Systems Pharmacology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0811-637X

  4. Timothy J Mitchison

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7781-1897

Funding

Japan Society for the Promotion of Science (H29-814)

  • Kenichi Shimada

National Institute of General Medical Sciences (R35GM131753)

  • Timothy J Mitchison

National Cancer Institute (U54-CA225088)

  • Jeremy L Muhlich

Defense Advanced Research Projects Agency (W911NF-15-1-0544)

  • John A Bachman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Erica A Golemis, Fox Chase Cancer Center, United States

Version history

  1. Received: March 20, 2020
  2. Accepted: February 6, 2021
  3. Accepted Manuscript published: February 8, 2021 (version 1)
  4. Accepted Manuscript updated: February 10, 2021 (version 2)
  5. 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.

Metrics

  • 21,833
    views
  • 1,278
    downloads
  • 51
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Kenichi Shimada
  2. John A Bachman
  3. Jeremy L Muhlich
  4. Timothy J Mitchison
(2021)
shinyDepMap, a tool to identify targetable cancer genes and their functional connections from Cancer Dependency Map data
eLife 10:e57116.
https://doi.org/10.7554/eLife.57116

Share this article

https://doi.org/10.7554/eLife.57116

Categories and tags

Research organism

Further reading

    1. Cancer Biology
    2. Cell Biology

    A syngeneic spontaneous zebrafish model of tp53-deficient, EGFRvIII, and PI3KCAH1047R-driven glioblastoma reveals inhibitory roles for inflammation during tumor initiation and relapse in vivo

    Alex Weiss, Cassandra D'Amata ... Madeline N Hayes
    Research Article

    High-throughput vertebrate animal model systems for the study of patient-specific biology and new therapeutic approaches for aggressive brain tumors are currently lacking, and new approaches are urgently needed. Therefore, to build a patient-relevant in vivo model of human glioblastoma, we expressed common oncogenic variants including activated human EGFRvIII and PI3KCAH1047R under the control of the radial glial-specific promoter her4.1 in syngeneic tp53 loss-of-function mutant zebrafish. Robust tumor formation was observed prior to 45 days of life, and tumors had a gene expression signature similar to human glioblastoma of the mesenchymal subtype, with a strong inflammatory component. Within early stage tumor lesions, and in an in vivo and endogenous tumor microenvironment, we visualized infiltration of phagocytic cells, as well as internalization of tumor cells by mpeg1.1:EGFP+ microglia/macrophages, suggesting negative regulatory pressure by pro-inflammatory cell types on tumor growth at early stages of glioblastoma initiation. Furthermore, CRISPR/Cas9-mediated gene targeting of master inflammatory transcription factors irf7 or irf8 led to increased tumor formation in the primary context, while suppression of phagocyte activity led to enhanced tumor cell engraftment following transplantation into otherwise immune-competent zebrafish hosts. Altogether, we developed a genetically relevant model of aggressive human glioblastoma and harnessed the unique advantages of zebrafish including live imaging, high-throughput genetic and chemical manipulations to highlight important tumor-suppressive roles for the innate immune system on glioblastoma initiation, with important future opportunities for therapeutic discovery and optimizations.

    1. Cancer Biology
    2. Cell Biology

    Cancer: Modeling glioblastoma

    Ian Lorimer
    Insight

    Establishing a zebrafish model of a deadly type of brain tumor highlights the role of the immune system in the early stages of the disease.

    1. Cancer Biology

    YAP/TAZ enhances P-body formation to promote tumorigenesis

    Xia Shen, Xiang Peng ... Chen-Ying Liu
    Research Article

    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.