Speaker
Description
Phenotypic plasticity underlies cancer progression and metastasis \cite{c1}, yet how distinct regulatory axes interact to shape tumour progression and patient outcomes remains unresolved. We investigated major axes of plasticity in ER-positive breast cancer, including metabolic reprogramming, epithelial-to-mesenchymal plasticity, and drug-resistance using ODE-based gene regulatory network simulations, integrative bulk and single-cell transcriptomic analyses, and patient survival analyses.
We show that the network exhibits multistability, organising into two mutually inhibiting modules of regulatory programs that define distinct attractor states. One module (favouring high glycolysis, mesenchymal/hybrid and tamoxifen-resistant phenotype) was found to be associated with aggressive disease progression and worse survival. On the other hand, the opposing module (favouring high oxidative phosphorylation, epithelial and tamoxifen-sensitive phenotype) correlated with better outcomes. Further, perturbations along one axis induced coordinated responses along other axes, indicating strong inter-axis coupling \cite{c2}.
Our findings establish phenotypic plasticity in cancer as an emergent property of coupled dynamical systems, suggesting that targeting regulatory interactions between axes can constrain transitions toward aggressive states \cite{c3}.
Bibliography
@article{c1,
title = {Phenotypic plasticity during metastatic colonization},
author = {Jehanno, Charly and Vulin, Milica and Richina, Veronica and Richina, Federica and Bentires-Alj, Mohamed},
journal = {Trends in Cell Biology},
volume = {32},
number = {10},
pages = {854--867},
year = {2022},
publisher = {Elsevier}
}
@article{c2,
title = {Interconnected axes of phenotypic plasticity drive coordinated cellular behaviour and worse clinical outcomes in breast cancer},
author = {Meena, Ritesh Kumar and Fan, Yijia and Ramu, Soundharya and Pandey, Anjaney J. and Kannan, Abhinav and Subramanian, Yashvita and Subramanian, Yukta and George, Jason T. and Jolly, Mohit Kumar},
journal = {bioRxiv},
year = {2025},
doi = {10.1101/2025.11.23.688595},
url = {https://www.biorxiv.org/content/early/2025/11/26/2025.11.23.688595}
}
@article{c3,
title = {Modulation of Network Plasticity Opens Novel Therapeutic Possibilities in Cancer, Diabetes, and Neurodegeneration},
author = {Kerest{\'e}ly, M{\'a}rk and Narozsny, Istv{\'a}n and Szarka, Levente and Veres, Daniel V. and Csermely, Peter and Keresztes, D{\'a}vid},
journal = {Advanced Science},
pages = {e22532},
year = {2026},
publisher = {Wiley}
}
