Unraveling Neural Circuitry in Peripheral Cancer Pathogenesis: From Local Innervation to Systemic Influences

项目摘要 协调癌症发病机制的复杂过程仍然不完全清楚。尽管大多数 研究集中在了解导致恶性肿瘤的遗传和表观遗传异常， 由于癌症的转化，现在已经很好地理解，癌症还整合了来自它们的各种输入。 微环境来指导他们的成长。从体内平衡到再生， 来维持每一个组织和细胞。因此，毫不奇怪，神经活动正在成为一个关键的 癌症生长的调节因子。我们最近发现大脑中的神经元活动严重影响大脑 癌症既通过旁分泌机制，更重要的是通过直接功能电化学 恶性细胞通过真正的神经元-胶质瘤突触整合到神经回路中。这些研究表明， 这是癌症生物学中一个未被充分认识的方面，它强调了脑癌的电成分。 神经胶质瘤细胞来源于各种神经前体细胞，有能力和机制， 神经信号，虽然令人惊讶，但确实扩展了它们拥有细胞类型的功能残留物的逻辑 他们从中脱颖而出。然而，非神经胶质源性肿瘤细胞类型是否具有类似的能力， 如果微环境的生物电状态类似地驱动肿瘤， 外周的发病机制仍有待阐明。本提案的目标是绘制和评估 外周肿瘤神经支配通过了解癌症之间的相互作用， 神经系统，以及与中枢神经系统（大脑）的系统性相互作用。因为有很多 在探索外周肿瘤神经支配的同时，我们将使用小细胞肺癌（SCLC）作为模型， 研究外周肿瘤如何在功能上整合到神经网络中。这一建议旨在了解 外周和中枢神经系统之间的局部和全身相互作用如何控制和改变 癌症生长的原发和继发部位的生物电状态影响肿瘤的发生，发展， 和转移。使用创新的经典和系统神经科学工具，我们将绘制动态神经回路 参与SCLC肿瘤神经支配，询问迷走神经活动（SCLC的主要脑神经） 外周神经系统）在细胞和分子水平直接影响肿瘤发病机制，评估如何 整个肺在肿瘤发生过程中发生生物电改变，并了解系统性 中枢神经系统、周围神经系统和肿瘤之间的动力学是协调的， 它们的活性促进癌症生长。因此，我们将癌症生物学的这种生物电特性扩展到一组新的生物电特性。 通过整体透镜观察恶性肿瘤-从分子到组织水平，从局部到全身 神经支配，并从启动转移;这种观点的电失调可能证明 通过确定使肿瘤正常化的新治疗靶点， 微环境和回答癌症神经科学这一新兴领域的基本问题。

Project Summary The complex processes orchestrating cancer pathogenesis remain incompletely understood. Though most studies have focused on understanding the genetic and epigenetic abnormalities leading to malignant transformation, it is now well understood that cancers additionally integrate various inputs from their microenvironment to instruct their growth. From homeostasis to regeneration, the nervous system is responsible for the maintenance of each tissue and cell. It is therefore no surprise that neural activity is emerging as a critical regulator of cancer growth. We have recently shown that neuronal activity in the brain heavily influences brain cancer both through paracrine mechanisms, and more importantly through direct functional electrochemical integration of malignant cells into neural circuitry via bona fide neuron-glioma synapses. These studies highlight an underappreciated aspect of cancer biology that emphasize the electrical component of cancers of the brain. The idea that glioma cells, derived from various neural precursor cells, have the ability and machinery to co-opt neural signals, though astonishing, does extend the logic that they possess functional remnants of the cell types from which they emerge. Yet, whether non-glial derived neoplastic cell types possess the ability to similarly interact with neural networks and if the bioelectric state of the microenvironment similarly drives tumor pathogenesis in the periphery remains to be elucidated. The goal of this proposal is to map and evaluate peripheral tumor innervation by understanding the reciprocal interactions between cancers, the local peripheral nervous system, and the systemic interactions with the central nervous system (the brain). As there is much to unravel while navigating peripheral tumor innervation, we will use small cell lung cancer (SCLC) as a model to investigate how peripheral tumors functionally integrate into neural networks. This proposal seeks to understand how local and systemic interactions between the peripheral and central nervous systems control and alter the bioelectric state of the primary and secondary sites of cancer growth to influence tumor initiation, development, and metastasis. Using innovative classic and systems neuroscience tools, we will map the dynamic neural circuits involved in SCLC tumor innervation, interrogate how vagal nerve activity (the main cranial nerve of the peripheral nervous system) directly affects tumor pathogenesis at the cellular and molecular level, assess how the lung as a whole is bioelectrically altered over the course of tumorigenesis, and understand if systemic dynamics between the central nervous system, the peripheral nervous system, and the tumor are coordinated in their activity to fuel cancer growth. We will thus extend this bioelectric property of cancer biology to a new set of malignancies viewed through a holistic lens - from the molecular to the tissue level, from local to systemic innervation, and from initiation to metastasis; this perspective of electric dysregulation may prove transformative for these intractable diseases by identifying novel therapeutic targets that normalize the tumor microenvironment and answer fundamental questions in this emerging field of cancer neuroscience.