Landscape of epithelial mesenchymal plasticity as an emergent property of coordinated teams in regulatory networks

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Abstract

Elucidating the design principles of regulatory networks driving cellular decision-making has fundamental implications in mapping and eventually controlling cell-fate decisions. Despite being complex, these regulatory networks often only give rise to a few phenotypes. Previously, we identified two 'teams' of nodes in a small cell lung cancer regulatory network that constrained the phenotypic repertoire and aligned strongly with the dominant phenotypes obtained from network simulations (Chauhan et al., 2021). However, it remained elusive whether these 'teams' exist in other networks, and how do they shape the phenotypic landscape. Here, we demonstrate that five different networks of varying sizes governing epithelial-mesenchymal plasticity comprised of two 'teams' of players - one comprised of canonical drivers of epithelial phenotype and the other containing the mesenchymal inducers. These 'teams' are specific to the topology of these regulatory networks and orchestrate a bimodal phenotypic landscape with the epithelial and mesenchymal phenotypes being more frequent and dynamically robust to perturbations, relative to the intermediary/hybrid epithelial/ mesenchymal ones. Our analysis reveals that network topology alone can contain information about corresponding phenotypic distributions, thus obviating the need to simulate them. We propose 'teams' of nodes as a network design principle that can drive cell-fate canalization in diverse decision-making processes.

Data availability

The current manuscript is a computational study. All raw numerical data used to generate the graphs is available at Dryad

The following data sets were generated

1. Jolly MJ
2. et al
(2022) Data from: v
Dryad Digital Repository, doi:10.5061/dryad.ncjsxksz7.

http://dx.doi.org/10.5061/dryad.ncjsxksz7

Article and author information

Author details

Kishore Hari

Centre for BioSystems Science and Engineering, Indian Institute of Science Bangalore, Bengaluru, India

Competing interests
The authors declare that no competing interests exist.
Varun Ullanat

Department of Biotechnology, RV College of Engineering, Bengaluru, India

Competing interests
The authors declare that no competing interests exist.
Archana Balasubramanian

Department of Biotechnology, PES University, Bengaluru, India

Competing interests
The authors declare that no competing interests exist.
Aditi Gopalan

Department of Biotechnology, RV College of Engineering, Bengaluru, India

Competing interests
The authors declare that no competing interests exist.
Mohit Kumar Jolly

Centre for BioSystems Science and Engineering, Indian Institute of Science Bangalore, Bengaluru, India

For correspondence
mkjolly@iisc.ac.in

Competing interests
The authors declare that no competing interests exist.

"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.

Copyright

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.