Glioma Tumors Hijack Healthy Mechanisms of Neuroplasticity in Order to Grow
Post by Trisha Vaidyanathan
The takeaway
Healthy neurons can form synapses with glioma tumor cells. These neuron-to-glioma synapses undergo a form of synaptic plasticity similar to healthy neurons, that is dependent on the release of brain-derived neurotrophic factor (BDNF), allowing tumor cells to proliferate and tumors to grow.
What's the science?
Gliomas are the most common form of brain cancer in children and adults and glioma tumor progression is highly regulated by the activity of surrounding neurons. However, it is not known precisely how neuronal activity regulates tumor progression. Neurons and glioma cells can interact through the secretion of signals and through direct neuron-to-glioma synapses. One hypothesis is that neuron-to-glioma synapses are strengthened through a form of neuroplasticity in which glioma cells increase their sensitivity to the excitatory neurotransmitter glutamate by recruiting more AMPA glutamate receptors to the membrane. This form of neuroplasticity can occur between two healthy neurons via the signaling molecule BDNF and the BDNF receptor, TrkB. This week in Nature, Taylor and colleagues used patient-derived glioma cells and mouse models to demonstrate that gliomas recruit BDNF signaling to strengthen the neuron-glioma connection and drive tumor proliferation and progression.
How did they do it?
First, the authors transplanted patient-derived glioma cells into mice, a process called xenografting. This allowed the authors to manipulate each component of the BDNF signaling pathway and assess the effect on tumor proliferation and animal survival. In a series of experiments, the authors (1) removed neuronal release of BDNF with a mutant mouse model, (2) used CRISPR to remove the BDNF receptor, TrkB, from the glioma cells, (3) administered a potential therapeutic drug (entrectinib) that blocks the family of Trk BDNF receptors, and (4) used pharmacology to block AMPA receptors.
Second, the authors directly tested whether BDNF drives plasticity in glioma cells by using patch-clamp electrophysiology to measure the glioma cell response to glutamate with or without BDNF and with or without the BDNF receptor.
Third, to assess whether glioma cell plasticity led to increased AMPA receptor signaling, the authors created cultures of the glioma cells and used a sophisticated method called cell-surface biotinylation to quantity the amount of AMPA receptor protein on the glioma membrane with and without BDNF exposure. Additionally, the authors used the pH-sensitive sensor, pHluorin, to visualize AMPA receptors moving to the membrane in real time after BDNF exposure.
Fourth, the authors assessed how well the glioma cells with or without the BDNF receptor were able to associate with the surrounding neuronal network by quantifying the number of neuron-to-glioma synapses with immuno-electron microscopy.
Lastly, the authors sought to validate their hypothesis that increased synapse strength led to higher tumor growth by stimulating glioma cells to varying degrees with optogenetics and measuring the resulting tumor growth.
What did they find?
First, the authors found that disrupting any part of the BDNF neuroplasticity pathway – either removing neuronal release of BDNF, removing or blocking the BDNF receptor in glioma cells, or blocking AMPA receptors – increased the survival of the xenografted mice and reduced tumor proliferation. This demonstrated that BDNF signaling is a critical component of how neuronal activity promotes tumor growth.
Second, the authors demonstrated that BDNF was sufficient to increase the glioma cell response to a puff of glutamate. Further, BDNF could not elicit this response if the glioma cell lacked the BDNF receptor TrkB confirming the importance of the BDNF-TrkB signaling pathway for glioma plasticity.
Third, the authors found increased AMPA receptor protein at the membrane of glioma cell cultures that were exposed to BDNF. They also were able to visualize AMPA receptors moving to the membrane after BDNF exposure in real-time with their pH-sensitive sensor. This confirmed that BDNF signaling in glioma cells drives neuroplasticity by increasing the number of AMPA receptors at the membrane, the same mechanism used by healthy neurons.
Fourth, immuno-electron microscopy revealed that glioma xenografts that lacked the BDNF receptor TrkB had fewer neuron-to-glioma synapses than xenografts that had TrkB expression. These data revealed that BDNF-TrkB not only strengthens the synapse but also promotes the formation of synapses.
Lastly, the authors clearly demonstrated the importance of neuron-to-glioma synapse plasticity for tumor growth by showing that robust optogenetic stimulation to depolarize glioma cells resulted in more tumor proliferation than mild optogenetic depolarization.
What's the impact?
The finding that glioma tumor cells hijack a well-established method of neuroplasticity to strengthen their integration into neuronal networks and proliferate is critical to our understanding of how brain cancer both influences and is influenced by, the surrounding healthy tissue. This work will provide several novel targets that could result in effective treatment for brain cancer, some of which the authors have already started to explore in this paper.
