USA research, published in Nature, shows how cancer cells exploit the nervous system to spread
“Having this work accepted for publication in Nature is a rare and significant accomplishment – one that reflects the power of a bold scientific idea, carried forward by hard work and perseverance,” said Christopher Davies, Ph.D.
By Carol McPhail
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Research conducted at the University of South Alabama provides new insight into how cancer cells exploit their microenvironment, especially nearby nerve cells, to grow and spread. The findings, published in the scientific journal Nature, will help scientists understand the complexity of cancer behaviors and could lead to new approaches for developing cancer therapies.
Simon Grelet, Ph.D., assistant professor of biochemistry and molecular biology at USA’s Frederick P. Whiddon College of Medicine, led the study. His team used innovative models to investigate how breast cancer cells interact with nerve cells and how that interaction contributes to cancer aggressiveness and metastasis.
“Our study revealed that the nervous system actively drives cancer progression by conferring adaptive advantages to tumor cells,” said Grelet, who conducts research at the USA Health Mitchell Cancer Institute. “We discovered that mitochondria transfer from neurons to cancer cells contributes to cancer cell survival under metastatic stress.”
Previous research revealed that breast cancer cells manipulate nerve cells and stimulate the growth of new neurons inside tumors. Clinical studies, meanwhile, showed that increased nerve density in tumors correlated with a worse prognosis in patients. Grelet and his team aimed to go further and determine how the neurons interacted with cancer cells to drive their aggressive behavior.
Christopher Davies, Ph.D., associate dean for research at the Whiddon College of Medicine, praised the research project as “a remarkable achievement.”
“Having this work accepted for publication in Nature is a rare and significant accomplishment – one that reflects the power of a bold scientific idea, carried forward by hard work and perseverance,” Davies said. “It also brings well-deserved recognition to the outstanding research being conducted at the Mitchell Cancer Institute.”
John V. Marymont, M.D., MBA, dean of the Whiddon College of Medicine and vice president for medical affairs, said the project represents an important step toward understanding cancer metastasis. “This research is a testament to the creativity, collaboration and perseverance of our faculty, whose work continues to influence the future of health care,” Marymont said. “We’re proud to see it published in such a respected journal.”
The project was a collaboration involving multiple institutions, including the research group led by Gustavo Ayala, M.D., professor in the Department of Pathology and Laboratory Medicine at McGovern Medical School / UTHealth in Houston.
“Dr. Ayala has pioneered the field of cancer innervation. His mentorship, insight, and contributions were invaluable to the success of this project,” said Grelet.
Mike Lin, Ph.D., professor of physiology and cell biology at the Whiddon College of Medicine, also contributed to the work.
Nerve signals and cancer metabolism
In one experiment, researchers used botulinum neurotoxin type A (Botox) to block communication between nerve cells and tumor cells in a breast cancer model. When neural signaling was disrupted, the tumors showed slower growth and reduced aggressiveness. High-throughput bioinformatics analyses revealed that this effect was linked to changes in cancer cell metabolism, suggesting that nerve signals play a critical role in boosting cancer cell energy production.
Using high-resolution microscopy, the team directly observed interactions between nerves and cancer cells in a novel nerve-cancer co-culture model they developed for this study. They found that neurons and cancer cells form intimate physical contacts, supporting the idea of active communication and even material exchange.
"One particularly striking characteristic of neuronal cells is their remarkably efficient metabolism,” Grelet said. “This is exemplified by the fact that, although the human brain represents only about 2% of total body weight, it accounts for approximately 20% to 25% of the body’s total energy consumption."
This metabolic efficiency is driven by mitochondria, tiny organelles that generate energy within cells. Grelet’s team discovered that cancer cells hijack mitochondria from neurons, enhancing their energy production and making them more aggressive.
Quantifying mitochondria transfer
To further study this phenomenon, the researchers employed flow cytometry and developed a custom software tool to quantify mitochondria DNA transfer between neurons and cancer cells. They found that blocking nerves in the primary tumor reduced mitochondria transfer between the host and the tumor by approximately 35%.
“This was remarkable considering that neurons represent only a small fraction of the total cellular population in the tumor,” Grelet said. “This disproportionate contribution underscores the central role of nerve-cancer interactions.”
One of the key challenges faced by the researchers was how to permanently track the mitochondria transfers. Grelet’s team developed a new synthetic biology tool called MitoTRACER that allowed them to label cancer cells that receive mitochondria from neurons by triggering a color change.
“Our development of the MitoTRACER genetic tool allows for the permanent marking of recipient cells that acquire mitochondria from donor cells, a technical advance that opens new avenues for studying intercellular mitochondria transfer in health and disease,” he said. A patent application for this technology is currently pending.
Implications for metastasis
Using MitoTRACER, they found that cancer cells containing the mitochondria transferred from neurons were more likely to show up in brain and lung metastasis. This suggested that the transferred mitochondria helped the cancer cells adapt to the harsh conditions of dissemination and adapt to distant environments.
“In fact, the vast majority of metastatic cancer cells fail to form distant metastases due to the stressors they encounter during dissemination,” Grelet said. “Identifying the mechanisms that allow some cells to overcome these challenges will help us target the subset of metastatic cells that succeed and prevent metastasis."
Investigating further, they found that the cells’ adaptability was due to superior metabolic fitness and plasticity. “Our findings suggest that instead of targeting highly motile cancer cells, we may need to shift our therapeutic strategies toward targeting cancer cells with this acquired metabolic plasticity,” he said.
Grelet credited current and former lab technicians for their contributions to the project: Gregory Hoover, Shila Gilbert, Olivia Curley and Clémence Obellianne.
The research was supported by funding from the National Institutes of Health, the Breast Cancer Research Foundation of Alabama, the Patricia Cobb Rodgers Endowment at the Mitchell Cancer Institute, and startup funds from the Department of Biochemistry and Molecular Biology at the Whiddon College of Medicine.
