Summary: Researchers have discovered that chronic physical pressure on the brain—such as the force exerted by an expanding tumor—does not just kill neurons through direct trauma. Instead, this mechanical stress activates a “self-destruction” program within the cells.
Using lab-grown neural networks and preclinical models, the study revealed that compression triggers a cascade of neuroinflammatory genes and stress-adaptive molecules. Even in neurons that initially survive the pressure, internal signaling for programmed cell death remains active, leading to irreversible damage that contributes to the cognitive and motor decline often seen in patients with brain tumors or traumatic injuries.
Key Facts
- Mechanical “Death Signals”: Chronic compression activates the AP-1 gene and HIF-1 molecules, which trigger neuroinflammation and signal for neurons to begin programmed self-destruction.
- Beyond the Tumor: The study highlights that while oncology often focuses on the tumor cells themselves, the mechanical force of the tumor’s expansion is a primary driver of damage to the surrounding healthy brain tissue.
- Disease Agnostic: Because the research focused on the mechanical physics of the brain, the findings could apply to various conditions involving pressure, including glioblastoma, traumatic brain injury (TBI), and hydrocephalus.
- Irreversible Loss: Since the brain cannot easily replace dead neurons, understanding these pressure-sensitive pathways is critical for developing neuroprotective therapies to prevent permanent sensory and motor loss.
Source: University of Notre Dame
To think, feel, talk and move, neurons send messages through electrical signals in the brain and spinal cord.
This intricate communication network is built of billions of neurons connected by synapses and managed and modified by glial cells. When neurons die, this communication network is disrupted and since this loss is irreversible, neuron death causes sensory loss, motor impairment and cognitive decline.
An interdisciplinary team of researchers from the University of Notre Dame is investigating the mechanisms of neuron death caused by chronic compression — such as the pressure exerted by a brain tumor — to better understand how to prevent neuron loss.
Published in the Proceedings of the National Academy of Sciences, their study found that chronic compression triggers neuron death by a variety of mechanisms, both directly and indirectly. The research is helping lay the groundwork for identifying therapies to prevent indirect neuron death.
“The impetus for this project was to figure out those underlying mechanisms. In cancer research, most researchers are focused on the tumor itself, but in the meantime, while the tumor is sitting there and growing, it’s damaging the organ that it’s living in,” said Meenal Datta, the Jane Scoelch DeFlorio Collegiate Professor of Aerospace and Mechanical Engineering at Notre Dame and co-lead author of the study.
“We fully believe that these growth-induced mechanical forces of the tumor as it expands is part of the reason we see damage in the brain.”
As an engineer who leads the TIME Lab, Datta studies the mechanics of tumors and the microenvironment, specifically for glioblastoma, an incurable brain cancer. She had found in prior work that tumors damage the surrounding brain. But to understand the mechanisms by which tumors kill neurons from compression alone, Datta needed a “hardcore neuroscientist.”
That neuroscientist is Christopher Patzke, the John M. and Mary Jo Boler Assistant Professor in the Department of Biological Sciences at Notre Dame and co-lead author of the study. Patzke utilizes induced pluripotent stem cells (iPSCs), which are either obtained from external sources or generated directly in his lab.
Unlike cells derived from fetal tissue, iPSCs are created by reprogramming a donor’s blood or skin cells — often collected during a routine medical visit.
These cells function like embryonic stem cells and can be differentiated or changed in the lab into any cell type in the body, including neurons.
For this study, iPSCs were used to create neural cells and develop a model system of neurons and glial cells that behave as a neuronal network would in the brain. Researchers grew the cells and then applied pressure to the system to mimic the chronic compression of a glioblastoma tumor.
After compressing the cells, graduate students Maksym Zarodniuk and Anna Wenninger, from Datta and Patzke’s labs respectively, compared how many neurons and glial cells died versus lived.
“For the neurons that are still alive, many of them have this programmed self-destruction signaling activated,” Patzke said. “We wanted to understand which molecular pathway was responsible for this; is there a way to save neurons from going down the drain to this cell death mechanism?”
By sequencing and analyzing all messenger RNA from the living neuronal and glial cells, the researchers found an increase in HIF-1 molecules, signalling for stress adaptive genes to improve cell survival, which leads to inflammation in the brain. The compression also triggered AP-1 gene expression, a type of neuroinflammatory response.
Both neurological reactions are indicators that neuronal damage and death is underway.
An analysis of data from the Ivy Glioblastoma Atlas Project shows that glioblastoma patients also reflect these compressive stress patterns and gene expression changes as well as synaptic dysfunction in line with the experiment’s results.
The researchers confirmed these results by mimicking force via a live compression system applied to preclinical models of brains.
Overall, the findings may help explain why glioblastoma patients experience cognitive impairments, motor deficits and elevated seizure risk. Additionally, the signaling pathways offer opportunities for researchers to explore as drug targets to reduce neuronal death.
“Our approach to this study was disease agnostic, so our research could potentially extend to other brain pathologies that affect mechanical forces in the brain such as traumatic brain injury,” Datta said.
“I’m all in on mechanics. Whatever it is that you’re interested in when it comes to cancer, above your question of interest, mechanics is sitting there and many don’t even know they should be considering it.”
The mechanics of compression and its effect on neuron loss is key for future research.
“Understanding why neurons are so vulnerable and die upon compression is critical to prevent excessive sensory loss, motor impairment and cognitive decline,” Patzke said. “This is how we will help patients.”
Funding: The study was funded by the National Institutes of Health and the Harper Cancer Research Institute (Harper) at Notre Dame. Additional funding and research support from Notre Dame was provided by the Berthiaume Institute for Precision Health (Berthiaume), the Genomics and Bioinformatics Core Facility, the Center for Research Computing, the Histology Core Facility and the Integrated Imaging Facility. Both Datta and Patzke are affiliated with Notre Dame’s Boler-Parseghian Center for Rare Diseases and the Warren Center for Drug Discovery.
Datta is a concurrent faculty member in the Department of Chemical and Biomolecular Engineering and faculty advisor for Notre Dame’s graduate programs in bioengineering and materials science and engineering. She is affiliated with Harper, the Eck Institute for Global Health, Berthiaume, NDnano and the Lucy Family Institute for Data & Society.
Patzke is a faculty advisor for Notre Dame’s graduate programs in biological sciences and integrated biomedical sciences as well as affiliated with the Center for Stem Cells and Regenerative Medicine.
Key Questions Answered:
A: It’s more than just weight; it’s about “compressive stress.” As a tumor grows, it physically squeezes the surrounding brain tissue. This pressure acts like a biological switch that tells healthy neurons to start a “self-destruct” sequence, even if the tumor hasn’t touched them yet.
A: That is the ultimate goal of this research. By identifying the specific molecular pathways (like HIF-1 and AP-1) that the pressure turns on, scientists hope to develop drugs that can “block” the self-destruct signal, keeping neurons alive even under mechanical stress.
A: Potentially, yes. The researchers describe their findings as “disease agnostic,” meaning the same self-destruction programming triggered by a tumor’s slow pressure might also be activated by the sudden, intense pressure of a traumatic brain injury or impact.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this brain cancer and neuroscience research news
Author: Meenal Datta
Source: University of Notre Dame
Contact: Meenal Datta – University of Notre Dame
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Mechanical compression induces neuronal apoptosis, reduces synaptic activity, and promotes glial neuroinflammation in mice and humans” by Maksym Zarodniuk, Anna Wenninger, Julian Najera, Jihaeng Lee, Jack Markillie, Cameron MacKenzie, Jenny Bergqvist-Patzke, Bianca Batista, Megna Panchbhavi, R’nld Rumbach, Alice Burchett, Charles Sander, Meenal Datta, and Christopher Patzke. PNAS
DOI:10.1073/pnas.2513172122
Abstract
Mechanical compression induces neuronal apoptosis, reduces synaptic activity, and promotes glial neuroinflammation in mice and humans
Mass effect, characterized by the compression and deformation of neural tissue from space-occupying lesions, can lead to debilitating neurological symptoms and poses a significant clinical challenge.
In the primary brain tumor glioblastoma (GBM), we have shown previously that compressive solid stress originating from the growing tumor reduces cerebral blood flow, leading to neuronal loss, increased functional impairment, and poor clinical outcomes.
However, the direct effects of compression on neurons and the underlying biophysical mechanisms are poorly understood.
Here, using multiscale compression systems and physiologically relevant in vitro and in vivo models, we find that chronic mechanical compression induces neuronal apoptosis and loss of synaptic puncta, leading to disrupted neural network activity, as assessed by calcium imaging.
This is accompanied by increased HIF-1 signaling and upregulation of downstream stress-adaptive genes in neurons.
We further show that chronic compression triggers AP-1–driven gene expression in glial cells, promoting a neuroinflammatory response.
Together, these findings reveal that solid stress directly contributes to neuronal dysfunction and inflammation caused by GBM by activating distinct pathways that can be targeted in future studies for neuroprotection.
