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.

Project Narrative Cancer remains a largely intractable disease; our finding that brain cancer integration into neural circuitry drives tumor progression brings up several questions regarding the role of the nervous system in malignancies outside of the brain. Here, we investigate the dynamic local and systemic crosstalk between cancers outside of the brain and both the peripheral and central nervous systems that collectively instruct primary and secondary cancer growth. Holistically mapping the circuits involved in the various stages of cancer pathogenesis, understanding how these circuit dynamics electrically alter the site of tumorigenesis, elucidating the subsequent downstream signaling in tumor cells as a result of membrane depolarization, and clarifying the systemic interactions between peripheral tumors and the brain all represent innovative questions to be answered by this proposal that offer a transformative approach to studying and effectively treating this group of devastating cancers.