Dynamic Interplay between Lower-Grade Glioma Instability and Brain Metaplasticity: Proposal of an Original Model to Guide the Therapeutic Strategy

SIMPLE SUMMARY: The behavior of diffuse lower-grade glioma (LGG) is changing over time, spontaneously, and in reaction to therapies. Due to genomic instability and clonal expansion, although LGG initially progresses slowly, the growth accelerates at the time of malignant transformation. Furthermore, its progression pattern may change by switching from a proliferative towards a more migratory profile. Along with glioma plasticity, the brain itself is constantly adapting to the tumor and treatment(s) thanks to reconfiguration within and between neural networks. The pattern of reallocation can also evolve, especially by shifting from perilesional to contrahemispheric functional reorganization: this reorientation of cerebral reshaping is related to metaplasticity. The interplay between LGG mutations and reactional connectomal rearrangement leads to perpetual modulations in the glioma–neural equilibrium, explaining the possible preservation of quality of life. An original model of these dynamic interactions across LGG plasticity and the brain metanetwork is proposed to guide a tailored step-by-step individualized management over years. ABSTRACT: The behavior of lower-grade glioma (LGG) is changing over time, spontaneously, and in reaction to treatments. First, due to genomic instability and clonal expansion, although LGG progresses slowly during the early period of the disease, its growth velocity will accelerate when this tumor will transform to a higher grade of malignancy. Furthermore, its pattern of progression may change following therapy, e.g., by switching from a proliferative towards a more diffuse profile, in particular after surgical resection. In parallel to this plasticity of the neoplasm, the brain itself is constantly adapting to the tumor and possible treatment(s) thanks to reconfiguration within and between neural networks. Furthermore, the pattern of reallocation can also change, especially by switching from a perilesional to a contrahemispheric functional reorganization. Such a reorientation of mechanisms of cerebral reshaping, related to metaplasticity, consists of optimizing the efficiency of neural delocalization in order to allow functional compensation by adapting over time the profile of circuits redistribution to the behavioral modifications of the glioma. This interplay between LGG mutations and reactional connectomal instability leads to perpetual modulations in the glioma–neural equilibrium, both at ultrastructural and macroscopic levels, explaining the possible preservation of quality of life despite tumor progression. Here, an original model of these dynamic interactions across LGG plasticity and the brain metanetwork is proposed to guide a tailored step-by-step individualized therapeutic strategy over years. Integration of these new parameters, not yet considered in the current guidelines, might improve management of LGG patients.