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

Author:

Hari Kishore1ORCID,Ullanat Varun2,Balasubramanian Archana3,Gopalan Aditi2,Jolly Mohit Kumar1ORCID

Affiliation:

1. Centre for BioSystems Science and Engineering, Indian Institute of Science Bangalore

2. Department of Biotechnology, RV College of Engineering

3. Department of Biotechnology, PES University

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.

Funder

Science and Engineering Research Board

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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