Topological signatures in regulatory network enable phenotypic heterogeneity in small cell lung cancer

  1. Lakshya Chauhan
  2. Uday Ram
  3. Kishore Hari
  4. Mohit Kumar Jolly  Is a corresponding author
  1. Indian Institute of Science, India

Abstract

Phenotypic (non-genetic) heterogeneity has significant implications for development and evolution of organs, organisms, and populations. Recent observations in multiple cancers have unravelled the role of phenotypic heterogeneity in driving metastasis and therapy recalcitrance. However, the origins of such phenotypic heterogeneity are poorly understood in most cancers. Here, we investigate a regulatory network underlying phenotypic heterogeneity in small cell lung cancer, a devastating disease with no molecular targeted therapy. Discrete and continuous dynamical simulations of this network reveal its multistable behavior that can explain co-existence of four experimentally observed phenotypes. Analysis of the network topology uncovers that multistability emerges from two teams of players that mutually inhibit each other but members of a team activate one another, forming a 'toggle switch' between the two teams. Deciphering these topological signatures in cancer-related regulatory networks can unravel their 'latent' design principles and offer a rational approach to characterize phenotypic heterogeneity in a tumor.

Data availability

Gene expression profiles of 52 SCLC cell lines were downloaded from Broad Institute's CCLE expression data. Data for GSE73160 was downloaded from NCBI website. All codes used to generate and analyze simulation data, and codes used to analyze gene expression data are available at : https://github.com/uday2607/CSB-SCLC

The following previously published data sets were used

Article and author information

Author details

  1. Lakshya Chauhan

    Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India
    Competing interests
    The authors declare that no competing interests exist.
  2. Uday Ram

    Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India
    Competing interests
    The authors declare that no competing interests exist.
  3. Kishore Hari

    Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India
    Competing interests
    The authors declare that no competing interests exist.
  4. Mohit Kumar Jolly

    Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India
    For correspondence
    mkjolly@iisc.ac.in
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6631-2109

Funding

Science and Engineering Research Board (SB/S2/RJN-049/2018)

  • Mohit Kumar Jolly

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

Reviewing Editor

  1. Sandeep Krishna, National Centre for Biological Sciences­‐Tata Institute of Fundamental Research, India

Version history

  1. Received: November 1, 2020
  2. Accepted: March 16, 2021
  3. Accepted Manuscript published: March 17, 2021 (version 1)
  4. Version of Record published: March 31, 2021 (version 2)

Copyright

© 2021, Chauhan 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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  1. Lakshya Chauhan
  2. Uday Ram
  3. Kishore Hari
  4. Mohit Kumar Jolly
(2021)
Topological signatures in regulatory network enable phenotypic heterogeneity in small cell lung cancer
eLife 10:e64522.
https://doi.org/10.7554/eLife.64522

Share this article

https://doi.org/10.7554/eLife.64522

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