Bridging brain and body in cancer

In this Outlook, Cross et al. comment on how methodological advances position us to better understand neuro–immune communication in acute and chronic diseases such as infection, inflammation and cancer.

Abstract

Recent work has highlighted the central role the brain–body axis plays in not only maintaining organismal homeostasis but also coordinating the body's response to immune and inflammatory insults. Here, we discuss how science is poised to address the many ways that our brain is directly involved with disease. In particular, we feel that combining cutting-edge tools in neuroscience with translationally relevant models of cancer will be critical to understanding how the brain and tumors communicate and modulate each other's behavior.

As highlighted throughout the 88th Cold Spring Harbor Laboratory Symposium on Brain Body Physiology, the axis between the brain and the periphery is not only the central regulator of whole-body physiology and behavior but also plays a key role in many systemic illnesses. Recent advances in optogenetics and chemogenetics, coupled with the advent of novel mouse models, have allowed researchers to map the circuitry that controls stereotypical reflex arcs and normal homeostatic processes involved in respiratory function, food intake and digestion, and heart rate (Prescott and Liberles 2022). Eloquent work presented at the symposium by Dr. Vineet Augustine and Dr. Yin Liu highlighted the role of vagal neurons in regulating the fainting reflex (Lovelace et al. 2023) and control of breathing (Liu et al. 2021), respectively, and concisely demonstrated how recent methodological advances can be applied to expand our understanding of homeostatic processes. These studies, in conjunction with others presented throughout the Symposium and recently published, have implicated neural input in the regulation of almost every physiological process at steady state, and recent work has begun to highlight the roles that brain–body circuits play in pathological conditions.

The interplay between the brain and the immune system has been extensively characterized. Neural circuits have been demonstrated to be activated by various inflammatory stimuli, driving canonical responses such as fever, sickness, and immune tolerance. Work presented at the Symposium and recently published by Dr. Charles Zuker's group have identified specific peripheral neuronal pathways that detect inflammation, transmitting this information to higher brain centers such as the nucleus of the solitary tract, which coordinates the corresponding immune response and the resolution of inflammation by transmitting signals to the periphery (Jin et al. 2024). As highlighted at the Symposium by Dr. Ruslan Medzhitov, in conditions such as infection and allergy, peripheral inflammatory signals are detected and transmitted to the brain by the vagus nerve, which in addition to serving as the main conductor of parasympathetic output to the heart, lungs, and digestive tract, also serves a principal role in sensing immune insults (Bin et al. 2023; Florsheim et al. 2023; Plum et al. 2023). In turn, peripheral immune activity detected and transmitted to the brain activates behavioral circuits involved in food aversion and sickness.

Our understanding of the neural pathways involved in infection and inflammation have been aided in part by the relative ease in integrating representative models of disease with animal models and genetic toolkits used frequently to map neural circuitry. For example, the atlas of Cre driver mouse lines has been expanded to cover practically all subsets of neurons in both the brain and the periphery. These mouse strains can be used in combination with genetic or viral expression of DREADDs or opsins to examine the functions of activating or inhibiting specific neuronal populations in disease by simply injecting these animals with an infectious agent or inflammatory stimulus such as LPS without the need for expansive genetic crosses or generation of new mouse models. While not perfect, animal models of infection and inflammation can accurately recapitulate features of human pathology, providing an avenue to translate any such findings into the clinic (Masopust et al. 2017).

In contrast to more acute conditions, the role of brain–body physiology in chronic diseases such as cancer remains understudied. Tumors are densely innervated and highly inflammatory, producing both localized and circulating mediators that can be detected by the peripheral and central nervous systems, respectively. There are many similarities in the immune phenotype between tumors and infections, including the recruitment of a diverse milieu of immune cells; protracted release of proinflammatory and anti-inflammatory mediators such as IL-6, TNFα, and IL-10; and localized destruction of tissue (Goldszmid et al. 2014). Additionally, tumor cells have been demonstrated to secrete neuromodulatory factors known to be important in peripheral immune sensing (Mancusi and Monje 2023).

Recent studies have begun to parse out how peripheral nerves interact with tumors to promote their initiation, growth, and metastasis. In high-grade gliomas, brain tumors directly synapse with surrounding neurons, with these tumor–neuron synapses directly promoting glioma growth and progression (Venkatesh et al. 2019). In models of prostate cancer, the autonomic nervous system plays a key role in both the initiation and dissemination of tumor cells (Magnon et al. 2013). To date, most studies investigating the neuron–oncology axis have been unidirectional, focusing on how nerves regulate tumor behavior and growth. In contrast, very few studies have examined the reverse signaling pathways, such as the signals sent from the tumor to surrounding nerve fibers and the effect these signals have in regulating behavioral and physiological responses in the body.

The centrally acting effects of tumors on the nervous system have been demonstrated in cancer-associated cachexia, which is a paraneoplastic syndrome characterized by extreme weight loss driven by the combination of reduced food intake and a switch to hypercatabolic metabolism. Cancer-associated cachexia involves a host of tumor cell-autonomous and nonautonomous factors that are released into circulation, driving catabolic changes in metabolic tissues as well as acting centrally in the area postrema and nucleus of the solitary tract to initiate behavioral symptoms such as loss of appetite, fatigue, and anhedonia. Such symptoms dramatically impair patients’ quality of life, leading to reduced physical, emotional, and social well-being and increased use of healthcare resources. There is thus a large clinical need to understand underlying mechanisms, identify biomarkers, and develop new therapeutic strategies to prevent and reverse cachexia.

Much of the focus of cachexia research has emphasized the role of circulating factors signaling directly to the brain. Work by many groups has identified circulating inflammatory factors that are capable of binding to receptors in the area postrema of the brainstem that consequently triggers behavioral changes including loss of food and water intake, decreased locomotor output, and ultimately, weight loss (Baracos et al. 2018; Sun et al. 2024). Such work was highlighted at the Symposium by Dr. Bo Li, whose group demonstrated that IL-6 detected by area postrema neurons in the brainstem is essential for the development of cachexia in a colon cancer model (Sun et al. 2024). It should be noted that many of these findings may be limited in part by reliance on subcutaneous tumor models using cell lines that do not accurately represent human disease. These tumor models develop rapidly, with cachexia often developing when tumors have reached a size of ∼2 g (this would be the equivalent of a bowling ball-sized tumor in humans). Additionally, implanting rapidly growing tumors in the flank is poorly representative of the insidious nature of human tumors, which grow slowly in the native environment of their tissue of origin and are densely innervated by projecting fibers from the vagus or dorsal root ganglia.

There are a vast number of similarities between sickness behaviors seen in animal models of infection and cancer-associated cachexia; namely, weight loss, reduced food and water intake, decreased movement, and general malaise. It has become evident that in models of infection and inflammation, these behaviors are driven in part by detection of local inflammatory signals by specific populations of innervating sensory neurons (Bin et al. 2023; Florsheim et al. 2023; Plum et al. 2023). Given the similarities in behavioral output between sickness and cachexia and the overlap of inflammatory stimuli between cancer and infection, it is our hypothesis that similar tumor–brain connections mediate cancer-associated sickness. The advent of genetically engineered mouse models that allow tumors to develop in an autochthonous setting serve as the ideal model to investigate the relationship between tumors and neural circuits. These models more accurately reflect each stage of human disease, developing over a similar time course and allowing for reflective changes in the tumor microenvironment.

Over 50% of cancer patients can develop cachexia, with many patients ultimately succumbing to cachexia rather than the underlying disease (Baracos et al. 2018). Given the dearth of effective treatment options for cachexia, there is a need to integrate cutting-edge tools in the field of brain–body physiology (chemo/optogenetics and genetically engineered mouse models) with the best animal models of cancer that accurately recapitulate features of human disease. Although laborious, such studies will be crucial to understanding the circuitry, both central and peripheral, between tumor and brain and identifying the classes of neurons that detect tumor-derived signals and how these signals are transmitted to higher-order processing centers in the brain. This will allow us to expand our understanding of conditions such as cachexia that clearly have a central neuronal component in regard to both behavioral changes and sympathetic output to tissues that are implicated in the disease. Although such information can be leveraged therapeutically, it can also be integrated with our findings from studies examining acute immune insults in the brain–body axis, providing important context as to how the brain responds to chronic inflammation.