A survey of optimal strategy for signature-based drug repositioning and an application to liver cancer
- Shanghai Jiao Tong University, China
- Huazhong University of Science and Technology, China
Abstract
Pharmacologic perturbation projects, such as Connectivity Map (CMap) and Library of Integrated Network-based Cellular Signatures (LINCS), have produced many perturbed expression data, providing enormous opportunities for computational therapeutic discovery. However, there is no consensus on which methodologies and parameters are the most optimal to conduct such analysis. Aiming to fill this gap, new benchmarking standards were developed to quantitatively evaluate drug retrieval performance. Investigations of potential factors influencing drug retrieval were conducted based on these standards. As a result, we determined an optimal approach for LINCS data-based therapeutic discovery. With this approach, homoharringtonine (HHT) was identified to be a candidate agent with potential therapeutic and preventive effects on liver cancer. The antitumor and antifibrotic activity of HHT was validated experimentally using subcutaneous xenograft tumor model and carbon tetrachloride (CCL4)-induced liver fibrosis model, demonstrating the reliability of the prediction results. In summary, our findings will not only impact the future applications of LINCS data but also offer new opportunities for therapeutic intervention of liver cancer.
Data availability
Sequencing data have been deposited in GEO under accession codes GSE180243 and GSE193897.All data generated or analysed during this study are included in the manuscript and supporting files.
-
A survey of optimal strategy for signature-based drug repositioning and an application to liver cancerNCBI Gene Expression Omnibus, GSE180243.
-
Gene expression profiles of 35 paired HCC and non-tumor tissues by RNA-seq dataNCBI Gene Expression Omnibus, GSE124535.
-
Next-generation characterization of the Cancer Cell Line Encyclopedia.Broad Institute Cancer Cell Line Encyclopedia (CCLE).
-
The Genotype-Tissue Expression (GTEx) projectGenotype-Tissue Expression (GTEx).
-
Gene expression data of human hepatocellular carcinoma (HCC)NCBI Gene Expression Omnibus,GSE14520.
-
Integrative omics analysis in HCC samples [mRNA expression]NCBI Gene Expression Omnibus, GSE84005.
-
Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinomaNCBI Gene Expression Omnibus,GSE6764.
-
Gene-expression profiles of hepatitis C-related, early-stage liver cirrhosisNCBI Gene Expression Omnibus, GSE15654.
-
Characterization of gene expression profile in HBV-related liver fibrosis patientsNCBI Gene Expression Omnibus, GSE84044.
-
Gene expression profile of liver tissue from carbon tetrachloride (CCl4)-treated mouse cultured ex vivoNCBI Gene Expression Omnibus, GSE71379.
-
Gene expression profiles of fractionated cells from cirrhotic rat liversNCBI Gene Expression Omnibus,GSE63726.
Article and author information
Author details
Funding
National Natural Science Foundation of China (81972208)
- Hui Wang
National Natural Science Foundation of China (82170646)
- Hualian Hang
Shanghai Natural Science Foundation (19ZR1452700)
- Hui Wang
The Interdisciplinary Program of Shanghai Jiao Tong University (YG2021ZD10)
- Hualian Hang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Arduino A Mangoni, Flinders Medical Centre, Australia
Ethics
Animal experimentation: All animals were manipulated according to protocols approved by the Shanghai Medical Experimental Animal Care Commission and Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine.
Version history
- Preprint posted: June 30, 2021 (view preprint)
- Received: July 2, 2021
- Accepted: February 16, 2022
- Accepted Manuscript published: February 22, 2022 (version 1)
- Version of Record published: March 3, 2022 (version 2)
Copyright
© 2022, Yang 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
-
- 2,981
- Page views
-
- 381
- Downloads
-
- 47
- Citations
Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.
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)
A survey of optimal strategy for signature-based drug repositioning and an application to liver cancer
eLife 11:e71880.
https://doi.org/10.7554/eLife.71880
Further reading
-
- Cancer Biology
- Cell Biology
Collective cell migration is fundamental for the development of organisms and in the adult, for tissue regeneration and in pathological conditions such as cancer. Migration as a coherent group requires the maintenance of cell-cell interactions, while contact inhibition of locomotion (CIL), a local repulsive force, can propel the group forward. Here we show that the cell-cell interaction molecule, N-cadherin, regulates both adhesion and repulsion processes during rat Schwann cell (SC) collective migration, which is required for peripheral nerve regeneration. However, distinct from its role in cell-cell adhesion, the repulsion process is independent of N-cadherin trans-homodimerisation and the associated adherens junction complex. Rather, the extracellular domain of N-cadherin is required to present the repulsive Slit2/Slit3 signal at the cell-surface. Inhibiting Slit2/Slit3 signalling inhibits CIL and subsequently collective Schwann cell migration, resulting in adherent, nonmigratory cell clusters. Moreover, analysis of ex vivo explants from mice following sciatic nerve injury showed that inhibition of Slit2 decreased Schwann cell collective migration and increased clustering of Schwann cells within the nerve bridge. These findings provide insight into how opposing signals can mediate collective cell migration and how CIL pathways are promising targets for inhibiting pathological cell migration.
-
- Cancer Biology
- Structural Biology and Molecular Biophysics
Abelson tyrosine kinase (Abl) is regulated by the arrangement of its regulatory core, consisting sequentially of the SH3, SH2, and kinase (KD) domains, where an assembled or disassembled core corresponds to low or high kinase activity, respectively. It was recently established that binding of type II ATP site inhibitors, such as imatinib, generates a force from the KD N-lobe onto the SH3 domain and in consequence disassembles the core. Here, we demonstrate that the C-terminal αI-helix exerts an additional force toward the SH2 domain, which correlates both with kinase activity and type II inhibitor-induced disassembly. The αI-helix mutation E528K, which is responsible for the ABL1 malformation syndrome, strongly activates Abl by breaking a salt bridge with the KD C-lobe and thereby increasing the force onto the SH2 domain. In contrast, the allosteric inhibitor asciminib strongly reduces Abl’s activity by fixating the αI-helix and reducing the force onto the SH2 domain. These observations are explained by a simple mechanical model of Abl activation involving forces from the KD N-lobe and the αI-helix onto the KD/SH2SH3 interface.
