Abstract SY12-02: Neural regulation of tumors and their microenvironment: Novel, actionable, hallmark of cancer
Authors: Amit Moran 
Published: June 2022

Abstract
The Hallmarks of Cancer provided a framework that has guided cancer research since it was first published. Although Hanahan and Weinberg highlighted the role of the tumor microenvironment, the existing hallmarks should be expanded to include another crucial aspect of the tumor microenvironment—the tumor-neural interaction. Traditionally, the nervous and immune systems have been viewed as functionally and anatomically distinct, even though they share a critical common task: to detect and respond to internal and external threats, whether physical, chemical, or biological. While the role of the immune system is well established in cancer, and both immune evasion and tumor-promoting inflammation are considered hallmarks of cancer, the nervous system is typically viewed as a tissue affected by cancer and as a conduit for the transmission of cancer-related pain and perineural invasion.
Recent work by us and others has shown that the nervous system plays several important roles in promoting tumor initiation, progression, and metastasis. By comparing the transcriptomes of cancer-associated trigeminal sensory neurons with those of endogenous neurons in mouse models of oral cancer, we identified an adrenergic differentiation signature. We showed that loss of TP53 leads to adrenergic transdifferentiation of tumour-associated sensory nerves through loss of the microRNA miR-34a. Tumor growth was inhibited by sensory denervation or pharmacological blockade of adrenergic receptors, but not by chemical sympathectomy of pre-existing adrenergic nerves. A retrospective analysis of samples from oral cancer revealed that p53 status was associated with nerve density, which was in turn associated with poor clinical outcomes. This crosstalk between cancer cells and neurons represents one mechanism by which tumor-associated neurons are reprogrammed towards an adrenergic phenotype that can stimulate tumor progression and is a potential target for anticancer therapy. These studies suggest that newly formed nerve fibers support both cancer cells and the tumor microenvironment. However, despite increasing recognition of tumor-associated neurogenesis—the formation of new nerve fibers—this topic has been relatively understudied.
In the last decade, emerging technologies have enabled us to bridge the gaps between cancer research and neuroscience and to take a glimpse into the roles of nerves and their supporting cells like Schwann cells, in cancer. Specifically, the development of spatial imaging and in vivo neural tracing and recording techniques removed some of the obstacles that impeded cancer neuroscience research, namely, our ability to capture phenotypes and functions in the tumor microenvironment (i.e., dendrites and axons, far away from the neuron cell body or soma) using high-dimensional labeling techniques (e.g., mass cytometry and multiplex immunofluorescence). Using these techniques, it has been shown that in many types of cancer, ablation of different portions of the nervous system prevents cancer development and progression. This process is similar to another microenvironmental hallmark of cancer—tumor angiogenesis, whereby tumors induce the growth of new blood vessels to supply them with oxygen and blood-borne nutrients. Importantly, neuromodulation with both genetic and pharmacologic approaches has been shown to affect not only tumor growth but also the antitumor immune response.
Neurogenesis should be recognized as a hallmark of cancer for two important reasons. First, doing so would establish the neo-neurogenic process as a highly relevant therapeutic target for both the prevention and treatment of cancer. Second, it would foster interdisciplinary crosstalk between two fields that traditionally have progressed along parallel paths. We have credentialed the neoneurogenic process as a highly relevant therapeutic target for both the prevention and treatment of cancer; hopefully, in the next decade we will see more clinical trials targeting the neural microenvironment of cancer aiming to prevent tumor’s development and progression and improve patient’s quality of life.
Citation Format: Moran Amit. Neural regulation of tumors and their microenvironment: Novel, actionable, hallmark of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY12-02.