CancerNeuroscience: Systematic dissection of the crosstalk between cancer and the nervous system

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Accumulating evidence has indicated a crucial role of the nervous system in cancer. Changes of the innervation landscape, significantly impacting cancer progression, have been observed in many cancer types. However, perturbations of neural activity have yielded incoherent results in distinct cancer types, and sometimes even in the same cancer type across different studies. This variability may be due to the limitations in the currently employed methodologies: the composition of cancer-innervating neurons has not been extensively profiled, and the standard methods used to manipulate neural activity, such as surgical denervation and pharmacological treatment, lack specificity and selectivity in both the location of the perturbation and types of neurons affected, which complicates the interpretation of results. On the basis of current evidence, we hypothesise that different subsets of neurons have distinct impact on cancer progression; therefore, selective manipulation of specific subsets of cancer-innervating neurons will be crucial to illustrate their functional roles in tumourigenesis. To overcome the limitations of the conventional approaches, we will systematically dissect the crosstalk between cancer and the nervous system by interrogating a panel of genetically engineered mouse models of cancer with contemporary neuroscience methodologies. We will first perform anatomic and molecular characterisation of tumour-innervating neurons, followed by functional investigation using well-established genetic tools, including optogenetics and chemogenetics, which will allow cell-type-and circuit-specific perturbations of neural activity at temporal and spatial resolutions that cannot be achieved by conventional surgical or pharmacological methods. With this cross-disciplinary approach, we aim to unveil potential common logic underlying the involvement of the nervous system in cancer progression, which may ultimately lead to breakthroughs in clinical cancer treatment.