Decoding the Crosstalk Between the Nervous System and Cancer
Understanding how the nervous system influences cancer growth, spread, and immune responses is a major challenge.
Understanding how neurons, neural circuits, and the nervous system influence cancer growth and spread is an emerging field and one of the toughest challenges in cancer research.
The InteroCANCEption team, funded by Cancer Grand Challenges—a global initiative co-founded by Cancer Research UK and the National Cancer Institute—is working to tackle this challenge.
“Within the last few years, people have really started to pay attention to the cancer neuroscience field,” Dr. Leanne Li, group leader at The Francis Crick Institute and leader of team InteroCANCEption, told Technology Networks.
Emerging research into the neural–cancer connection
While the interactions between neurons and cancer cells have been extensively studied for brain cancers like glioblastoma in recent years, the role of the nervous system in peripheral cancers is less well understood.
The nervous system
The nervous system is shaped by neuronal activity and controls homeostasis, regeneration, plasticity, and organ function. The central nervous system (CNS) consists of the brain and spinal cord, and the peripheral nervous system (PNS) includes all nerves outside of the CNS, acting as a link between the CNS and sensory receptors, limbs, and organs.
Both the CNS and PNS can influence cancer initiation, progression, growth, and metastasis. Cancer cells can also influence the nervous system in return.
“When we look at tumors, they interact directly with the peripheral nervous system to impact cancer biology,” explained Li. The PNS communicates extensively with the CNS, and the tumor can also indirectly affect the CNS through secreted factors.
Innervation—the presence of nerves in the tumor microenvironment—is associated with poor outcomes in many cancers. Nerves in tumors can regulate oncogenic processes necessary for growth and spread, such as angiogenesis and extracellular matrix remodeling.
The nervous system also influences the immune system, affecting immunosurveillance and immune responses directed against cancer cells.
Li and her team recently demonstrated that sensory nerves in the tumor microenvironment actively support cancer growth, and that lung tumors, in turn, influence the growth and activity of these nerves. Chemical messengers from those nerves were seen to interfere with the immune response to the tumor. They also revealed that cigarette smoke, one of the biggest risk factors for lung cancer, increased neuronal activity and accelerated tumor progression through this neuroimmune pathway.
Furthermore, tumor cells can affect neighboring neurons by altering their structure, enhancing their function, or inducing a phenotypic switch, thereby promoting cancer growth through neuron- or nerve-derived mediators.
Li’s team also hypothesizes that the autonomic nervous system—part of the PNS that regulates involuntary processes—can mediate both local and systemic effects associated with cancer, including immune and metabolic processes.
“We propose that the sensory arm of the PNS detects how the tumors progress and sends a message to the brain,” she explained. “Then the brain will integrate and respond via the autonomic nervous system. We aim to elucidate these processes in the Cancer Grand Challenges project.”
The autonomic nervous system can coordinate many aspects of physiology, so identifying how responses differ between cancer types and subtypes is of particular interest.
A previously overlooked aspect of cancer biology
Despite the first observations of the nervous system’s influence on cancer dating back to the 19th century, “cancer neuroscience” was only established as an active field of research in 2019, following pioneering work in glioma.
One reason cancer neuroscience might have been overlooked for so long lies in the techniques used to study tumors. The traditional way to detect cancer is through histology of biopsy samples. In these small sections of tumors, the nerves present are barely visible.
“A special type of staining is needed to see the nerves, which is not a common practice in pathology,” explained Li. “In addition, bulk RNA sequencing of the tumor microenvironment cannot detect the neurons, because, while they extend fine axons into the tumor, their cell bodies are located far away.” Furthermore, proper methodology to fine-tune neuronal activity has only become available in recent years.
“You can’t know how nerves interact with cancer cells if you cannot even assess them with your methodology.” — Dr. Leanne Li
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Breakthroughs in single-cell sequencing, imaging, neurotechnology, and spatial omics are now enabling researchers to appreciate the contributions of the nervous system to cancer biology.
“We’re trying to figure out whether there are rules we can follow to predict or make sense of why different tumor types interact differently with different nerves,” Li said. “I think now is the right time for everything to come together.”
One major challenge in the field of cancer neuroscience is the complexity of the nervous system. “We’re dependent on neurobiologists to map out what is going on both in the brain and in the peripheral nervous system, so we can see what is altered in tumor conditions,” said Li. “They are making unprecedented progress, but we don’t have a clear roadmap yet.”
“We have world-leading neuroscientists in our team. The generous support from Cancer Grand Challenges will enable them to make breakthroughs in that field first, and then we can apply that to cancer immediately,” she continued.
Studying cancer–nervous system–brain crosstalk
Li’s team is using genetically engineered mouse models (GEMM) and GEMM-derived cell lines in their research, which allow them to investigate the cancer–nervous system crosstalk in models. “Having intact nervous and immune systems is indispensable,” she said.
Notably, unlike transplantation models, in which tumor cells are introduced into animals, GEMMs of cancer mimic how cancer develops in humans. This enables Li and her team to observe how cancer cells and the nervous system interact during different steps of tumorigenesis.
“Marrying sophisticated mouse modeling of cancer with cutting-edge neurobiology techniques and knowledge that our neuroscientist colleagues bring to the team will be the cornerstone for the success of this project.” — Dr. Leanne Li
A new approach for cancer treatments
Understanding the crosstalk between cancer and the nervous system could open the door for new cancer therapies.
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“I like to draw this analogy of cancer and the immune system,” explained Li. “I think that, in the past few decades, cancer immunotherapy has been the most exciting breakthrough in cancer drug discovery, and I think that cancer neuroscience could offer a similar opportunity to change the cancer field.”
While the nervous system and immune system have long been studied independently, research in the neuroimmunology field in the past decade demonstrated ample evidence that the nervous system actually cooperate to respond to tissue injury and fight infections.
“If we view the nervous system as a conductor of the symphony of our body physiology, it could conduct an immune reaction against tumors, which could be combined with immunotherapy to better treat cancer patients.” — Dr. Leanne Li
“Our view is that there are a lot of immunotherapies that don’t really work because either the tumor microenvironment, the macroenvironment, or the systemic impact isn’t quite right,” Li explained. “So we’re asking: is it possible to change the host macroenvironment or microenvironment by changing the nervous system? We may then be able to turn immune-cold tumors into immune-responsive tumors to facilitate immunotherapies.”
Neural modulation strategies could also eventually form a new approach to cancer treatment. Through a variety of techniques, including electrical stimulation, optogenetics, and chemogenetics, neuromodulation modifies nerve activity.
“Back in 1979, Francis Crick mentioned that the biggest challenge in neuroscience research is finding a way to control different types of neurons, specifically,” noted Li. “Now we finally have the knowledge and tools to manipulate neurons with greater molecular precision.”
There is substantial molecular diversity within populations of peripheral nervous system neurons. “Each sub-population has a distinct function corresponding to its molecular subtype,” explained Li. “With this diversity in mind, we are aiming to understand how different subtypes interact or are impacted by cancer progression.”
Once the team has identified neural subtypes of interest in cancer development and progression, they could develop drugs that specifically target these subtypes.
“There are also neural prosthetic devices through which we also hope to achieve local targeting,” said Li. “Rather than systemic manipulation, we want to know whether we can target neurons locally.”
“It’s a little bit premature for now, but that’s the goal—we want to achieve better neural targeting specificity, either with small molecules or neuroprosthetic devices.”
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