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

癌症神经科学：系统剖析癌症与神经系统之间的相互作用

• 批准号: EP/X020436/1
• 负责人: Leanne Li
• 金额: $ 164.72万
• 依托单位: The Francis Crick Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX020436%2F1
• 关键词: CancerNeuroscience; Systematic; dissection; crosstalk; between

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.

越来越多的证据表明，神经系统在癌症中起着至关重要的作用。在许多癌症类型中观察到神经支配景观的变化，显著影响癌症进展。然而，神经活动的扰动在不同的癌症类型中产生了不一致的结果，有时甚至在不同的研究中出现相同的癌症类型。这种变异性可能是由于目前采用的方法的局限性：癌症神经支配神经元的组成尚未得到广泛的分析，以及用于操纵神经活动的标准方法，如手术去神经支配和药物治疗，在扰动的位置和受影响的神经元类型方面缺乏特异性和选择性，这使结果的解释复杂化。根据目前的证据，我们假设不同的神经元子集对癌症进展有不同的影响;因此，选择性操纵特定的癌症神经元子集将是至关重要的，以说明它们在肿瘤发生中的功能作用。为了克服传统方法的局限性，我们将系统地剖析癌症和神经系统之间的串扰，通过用当代神经科学方法询问一组基因工程小鼠癌症模型。我们将首先进行肿瘤神经支配神经元的解剖和分子表征，然后使用成熟的遗传工具进行功能研究，包括光遗传学和化学遗传学，这将允许在时间和空间分辨率下对神经活动进行细胞类型和回路特异性扰动，这是传统手术或药理学方法无法实现的。通过这种跨学科的方法，我们的目标是揭示神经系统参与癌症进展的潜在共同逻辑，这可能最终导致临床癌症治疗的突破。