Environment-Dependent Modes of Adaptive Evolution in Neuroblastoma: Plasticity as a Selectable Trait. Roux C, Hamer S, and Shea A, et al., 2025. https://www.biorxiv.org/content/10.1101/2023.12.07.570359v1

The following Zenodo archive details data files used to conduct computational analysis of all components linked to sequencing. Code and scripts associated with this analysis can be found on the following Github Repository: https://github.com/PCEBrunaLab/Roux-et-al.-2024/. Neuroblastoma, like many aggressive cancers, exhibits phenotypic heterogeneity, contributing to therapy resistance and disease progression. However, direct evidence of how phenotypic plasticity influences tumour evolution remains limited. Using a multi-resolution quantitative approach, we define the principles, types, and dynamics of plasticity in neuroblastoma at unprecedented resolution. We demonstrate that intrinsic plasticity is a model-dependent process that enables the coexistence of drug-sensitive and drug-resistant states in environmentally stable conditions, positioning plasticity as a bet-hedging strategy that allows tumours to anticipate environmental changes. Additionally, we show plasticity varies across lineages and single-cell-derived clones, establishing that it is not merely an induced response but a heritable and selectable trait. By simultaneously mapping plasticity at and clonal dynamics in evolving neuroblastoma populations, we show plasticity is shaped by selective pressures, reinforcing its role as a fundamental driver of neuroblastoma evolution in a treatment- and genetic background-dependent manner. We define three distinct modes of plasticity- led adaptation. In the selection of the plasticity model, strong selective pressure temporarily constrains phenotypic transitions, but they reemerge with greater dynamics once the stressor is removed, favouring the selection of highly plastic clones. In the adaptive plasticity model, phenotypic transitions actively reshape tumour heterogeneity, allowing for rapid adaptation to treatment while minimising the impact of clonal selection. Finally, in the plasticity equilibrium model, phenotypic transitions persist at baseline, maintaining a state of phenotypic fluidity, with clonal selection ultimately dictating tumour evolution. These findings highlight the diverse, context-dependent strategies that neuroblastoma populations employ to navigate selective pressures and therapy resistance, emphasizing the need for plasticity-targeting therapeutic approaches to disrupt tumour adaptation and improve treatment outcomes.