# Cancer Neuroscience: Linking Neuronal Plasticity with Brain Tumor Growth and Resistance

## TL;DR

This review explores how brain tumor growth and resistance are linked to neuronal plasticity, suggesting new treatment strategies by integrating neuroscience and oncology.

## Contribution

The paper introduces cancer neuroscience as a novel framework linking neuronal plasticity to brain tumor progression and therapy resistance.

## Key findings

- Neuronal plasticity and signaling pathways like MAPK and PI3K/AKT contribute to brain tumor growth and resistance.
- Tumor cells exploit synaptic input and neurotransmitter signaling to integrate into neural circuits.
- Therapeutic strategies targeting neuronal plasticity include neuromodulation and computational modeling.

## Abstract

Brain tumors, particularly glioblastoma, are among the most aggressive and treatment-resistant malignancies of the central nervous system. While traditional research has focused primarily on genetic mutations and oncogenic signaling pathways, recent discoveries demonstrate that neuronal activity and neuronal plasticity actively contribute to tumor growth, invasion, and resistance to therapy. This review highlights the emerging field of cancer neuroscience, focusing on how pathological reprogramming of neuronal plasticity supports brain tumor progression. In addition, we discuss key mechanisms linking neuronal signaling to oncogenic pathways, including MAPK and PI3K/AKT, as well as the contributions of astrocytes, microglia, and other components of the tumor microenvironment. By highlighting future directions involving connect-omics and brain organoid platforms, this review aims to provide a conceptual framework for translating cancer neuroscience insights into novel, mechanism-based therapies for brain tumors.

Brain tumors, particularly glioblastoma, remain among the most lethal cancers, with limited survival benefits from current genetic and molecular-targeted approaches. Emerging evidence reveals that beyond oncogenes and mutations, neuronal plasticity, long-term potentiation, synaptic remodeling, and neurotransmitter-driven signaling play a pivotal role in shaping tumor progression and therapeutic response. This convergence of neuroscience and oncology has given rise to the field of cancer neuroscience, which explores the bidirectional interactions between neurons and malignant cells. In this review, we summarize fundamental principles of neuronal plasticity, contrasting physiological roles with pathological reprogramming in brain tumors. We highlight how tumor cells exploit synaptic input, particularly glutamatergic signaling, to enhance proliferation, invasion, and integration into neural circuits. We further discuss how neuronal-driven feedback loops contribute to therapy resistance, including chemoresistance, radioresistance, and immune evasion, mediated through pathways such as mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), and calcium influx. The tumor microenvironment, including astrocytes, microglia, and oligodendrocyte-lineage cells, emerges as an active participant in reinforcing this neuron-tumor ecosystem. Finally, this review explores therapeutic opportunities targeting neuronal plasticity, spanning pharmacological interventions, neuromodulation approaches (transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), optogenetics), and computational/artificial intelligence frameworks that model neuron tumor networks to predict personalized therapy. Also, we propose future directions integrating connect omics, neuroinformatics, and brain organoid models to refine translational strategies.