To be or not to be: Uncovering the Interplay between Phenotypic Robustness and Plasticity in Gene Regulatory Networks.

Cancer is a complex disease characterized by uncontrollable cell proliferation and the ability of cells to colonize multiple organs in the body through a process called metastasis. Metastatic cells must adapt dynamically 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 important properties of metastatic cells facilitate this dynamic adaptation: phenotypic plasticity and phenotypic robustness. Phenotypic plasticity is the ability of cells to adapt dynamically to their environment by acquiring appropriate phenotypes, such as immune evasion and adhesion to the surroundings during colonization and lack thereof during migration. On the other hand, phenotypic robustness refers to the ability of cells to maintain their phenotypes that are conducive to their survival despite environmental fluctuations. Although these two properties have conflicting natures, a balance between the two is necessary for successful metastasis.



We analyze gene regulatory networks underlying metastasis better to understand the emergence of phenotypic plasticity and robustness. Specifically, we focus on the complex gene-regulatory networks underlying Epithelial-Mesenchymal Plasticity (EMP), a critical process in metastasis. Our research reveals that the topological traits of these networks hold key information for explaining these emergent properties. While plasticity and robustness have an antagonistic relationship, common topological features such as positive feedback loops support both properties. These features are uniquely enriched in biological networks, indicating their evolutionary importance.



Our findings offer new avenues for developing therapeutic targets to control plasticity and, thereby the metastatic potential of cancer cells. By targeting the positive feedback loops that support both plasticity and robustness, it may be possible to reduce the ability of cancer cells to adapt to their environment and colonize distant organs in the body. Our findings could have significant implications for developing new cancer treatments that are more effective and targeted.