Wired for danger: Revealing the neural secrets of melanoma metastasis

Melanoma, although it accounts for only a small percentage of skin cancers, is responsible for the majority of skin cancer deaths. With the number of melanoma cases rising sharply in recent years, early detection is becoming increasingly critical. While current methods rely on visual examinations and advanced imaging techniques, there is growing interest in understanding the role of the nervous system in cancer development. Surprisingly, tumors have their own network of nerves, and these nerves could be key to discovering new ways to predict how dangerous a melanoma can become.

Understanding the intricate behaviors of tumors has long been a goal for cancer researchers. Recent findings from Case Western Reserve University reveal great progress in differentiating melanomas based on their metastatic potential through neuronal recordings. The research, led by Dr Grant McCallum and Professor Dominique Durand, along with Jay Shiralkar and Tiana Anthony, uncovers how neuronal activity within tumors correlates with their metastatic behavior. Their study, published in PLOS ONE, marks a significant step toward early detection and treatment of melanoma.

The researchers performed a series of experiments in mice to observe neuronal patterns in metastatic and non-metastatic melanomas. Professor Durand explained the motivation behind the study: “Our goal was to determine whether the bioelectrical behavior of tumors could serve as an early indicator of their metastatic potential.”

To explore differences in neuronal activity between various types of melanomas, the research team used a combination of advanced neuronal recording techniques and bioluminescent imaging. They implanted electrodes into mouse tumors to monitor neuronal spikes, providing a real-time view of electrical activity within the tumors. This allowed the team to capture detailed neural patterns and correlate them with the behavior of the tumors over time. Daily records were taken to ensure that the data reflected ongoing changes within the tumor environment.

The team found that melanomas with high metastatic potential exhibited significantly higher neuronal activity compared to those with low metastatic potential. This activity was particularly evident in the spikes observed in the neuronal recordings. Tumors with metastasis showed discontinuous trains of high neuronal activity, while tumors without metastasis exhibited minimal neuronal spikes. In simpler terms, more aggressive tumors had more “active” nerves within them. The presence of sympathetic nerves played a crucial role in this activity. “Sympathectomy, or chemical removal of sympathetic nerves, eliminated maximal neuronal activity in both sexes,” noted Dr. McCallum, emphasizing the importance of these nerves in tumor progression. “Surprisingly, our research indicates that the brain is not only aware of the presence of a tumour, but also establishes lines of communication to control it. The intricate neural activity we observed within melanomas suggests a complex interplay where the brain could influence tumour behaviour and progression,” explained Professor Dominique Durand.

In addition to neural recordings, the researchers used bioluminescent imaging to track tumor growth and metastasis. By injecting a bioluminescent tracer, they were able to visualize the expansion of the tumors and their spread to other parts of the body, particularly the cranial area, which is a common site of melanoma metastasis. This method provided a comprehensive view of how the tumors developed and spread over time. The team observed that peaks in neural activity closely aligned with the onset of increased metastatic burden, underscoring the potential of neural recordings as a predictive tool.

Additionally, the study found that tumors with low metastatic potential had significantly lower nerve density compared to their highly metastatic counterparts. This difference in nerve density further solidifies the link between neuronal activity and tumor aggressiveness.

The researchers believe that this study opens new avenues for early diagnosis and targeted therapy in the treatment of melanoma. “Our findings suggest that monitoring neuronal activity in tumours could provide a non-invasive method to predict their metastatic potential,” said Professor Durand. “This approach could lead to earlier interventions, which could improve survival rates for melanoma patients.”

In conclusion, the study by Dr McCallum, Professor Durand and colleagues presents compelling evidence that neuronal recordings can distinguish between melanomas based on their metastatic potential. This advance not only improves our understanding of tumor biology, but also paves the way for innovative diagnostic tools in cancer treatment.

Journal reference

Shiralkar, J., Anthony, T., McCallum, G. A., & Durand, D. M. (2024). Neuronal recordings can differentiate between melanomas that metastasize spontaneously and melanomas with low metastatic potential. MORE ONE, 19(2), e0297281. DOI: https://doi.org/10.1371/journal.pone.0297281

About the authors

Grant A. McCallum He received his Ph.D. degree in electrical engineering from Case Western Reserve University (CWRU) in 2011. He is currently a Research Assistant Professor in the Department of Biomedical Engineering at CWRU. Prior to graduate studies, he worked for a total of nine years at Texas Instruments and nVidia Corporation as a Senior ASIC Design Engineer creating broadband access integrated circuits and graphics processors. His general research interests include the development of peripheral nerve interfaces, low-noise neural recording systems, and implantable biotelemetry devices.

Dominique M. Durand is the EL Linsed Professor of Biomedical Engineering and Neurosciences and director of the Center for Neural Engineering at Case Western Reserve University in Cleveland, Ohio. He received a degree in engineering from the Ecole Nationale Superieure d'Electronique, Hydrolique, Informatique et Automatique of Toulouse, France, in 1973. In 1974, he received a master's degree in Biomedical Engineering from Case Reserve University in Cleveland, Ohio, working for several years at the Addiction Research Foundation of Toronto, Canada, and in 1982 received a PhD in Electrical Engineering from the Institute of Biomedical Engineering at the University of Toronto. He received a Presidential Young Investigator Award from the NSF, as well as the Diekhoff and Wittke awards for undergraduate and graduate teaching and the Mortar board top-prof awards from Case Western Reserve University. He is a member of the IEEE and also a member of the American Institute of Medical and Biomedical Engineering and a member of the Institute of Physics. He serves on many editorial boards of peer-reviewed scientific journals. He is the founding editor of the Journal of Neural Engineering and served as editor-in-chief for 18 years. His research interests focus on neural engineering and include computational neuroscience, neurophysiology and control of epilepsy, nonlinear dynamics of neural systems, neural prostheses, and applied interactions of magnetic and electric fields with neuronal tissue. He has obtained funding for his research from the National Science Foundation, the National Institutes of Health, and private foundations. He has published more than 160 peer-reviewed articles and has consulted for many biotechnology companies and foundations.

Dr. Jay R Shiralkar He recently earned his PhD in Biomedical Engineering from Case Western Reserve University under the guidance of eminent and distinguished personalities. Professor Dominique M Durand. His research focused on the development of neural interfaces for solid tumors, with an emphasis on unraveling the role of the autonomic nervous system in tumor physiology. During his PhD studies, Jay published articles in peer-reviewed journals, highlighting his contributions to the field of neural engineering and cancer biology and their applications in breast tumors and melanoma.

Jay's work has been recognized with awards, including the Swanger Fellowship Award from the Case School of Engineering. He has also presented his findings at multiple international conferences, earning him recognition for his novel approaches to solving complex biomedical problems.

Beyond his research, Jay has demonstrated a strong commitment to mentoring and teaching, serving as a TA for several undergraduate courses and mentoring junior researchers in the lab. His dedication to education and innovation in biomedical engineering positions him as a promising emerging leader in this field.

In his free time, Jay enjoys volunteering with community health initiatives and exploring the latest advances in medical technology. With a passion for improving patient outcomes through cutting-edge research, Dr. Jay R Shiralkar is poised to make significant contributions to the oncology and biomedical engineering community.