Alladi Ramakrishnan Hall

Design principles of phenotypic plasticity and robustness in gene regulatory networks underlying cancer metastasis

Kishore Hari

Centre for BioSystems Science and Engineering, IISc, Bengaluru

Metastasis is a complex process that involves cancer cells adapting to different biochemical and biomechanical changes in their environment as they migrate through tissue barriers, travel through the bloodstream, and colonize distant sites in the body. Two key properties that enable cancer cells to survive metastasis are phenotypic plasticity and phenotypic robustness. Phenotypic plasticity is the ability of cells to change their phenotype in response to changes in their environment, while phenotypic robustness is the ability of cells to maintain their phenotype despite environmental fluctuations. The balance between these properties is crucial for successful metastasis, but it is not fully understood. Our study focuses on the gene regulatory networks that regulate phenotypic plasticity and robustness in the context of Epithelial-Mesenchymal Plasticity (EMP), a critical process in metastasis. We demonstrate that phenotypic plasticity and robustness emergent from these networks have an antagonistic relationship across a wide range of parameter sets. However, both properties are support by a balanced abundance of positive and negative feedback loops. We further find that higher level topological features – teams of nodes – emerge from a unique construction of feedback loops that can maintain a balance between plasticity and robustness. These features are important for evolution and are uniquely enriched in biological networks. Our findings pave way towards new therapeutic targets for reducing metastasis potential by controlling phenotypic plasticity and reducing phenotypic robustness through the regulatory network topology.