The Neural Regulation of Small Cell Lung Cancer Progression
Abstract
Lung cancers are the leading cause of cancer-related death. Small cell lung cancer (SCLC) is a particularly aggressive subtype accounting for about ~15% of all lung cancers. Compared with civilians, military personnel are at higher risk for being diagnosed with this type of lung cancer in part due to occupational exposure to inhaled carcinogens. Yet, due to their limited occurrence and stigmatic association with tobacco and cigarette use, SCLC is often not prioritized in research. As treatment options are currently limited due to the large metastatic burden and advanced stage at the time of diagnosis, SCLC remains one of the most intractable human cancers, demanding a fundamental change in our approach to therapy. Thus, defining how these malignant cells interact with their microenvironment is crucial to understanding the fundamental factors contributing to this disease pathology. My past work has illustrated that one critical microenvironmental dependency of cancer cells is their direct integration into neuronal circuitry. We have found that neuronal activity promotes brain cancer progression, which highlights the previously unexplored potential to target neuron-cancer circuit dynamics for therapy of these lethal cancers. My work has led us to the startling realization that cancers can functionally integrate into electrically active neuronal circuits, which has already led to an ongoing clinical trial. We have thus uncovered that cancers are electrically active – a new and fundamental property of cancer pathophysiology that has largely shifted our view of malignant tissue. Effective therapy for these cancers may thus require targeting not only molecular mechanisms of cell proliferation, but also functional/structural neuron-cancer interactions. As small cell lung cancer (SCLC) originates from neuroendocrine cells in the lung and exhibit several neural-like properties, it stands to reason that these cancers similarly benefit from direct neuronal input. This has been hypothesized in the literature, but has been a vastly understudied area of research due to communication barriers between cancer biologists, neuroscientists, and lung biologists. Understanding the neurobiological aspects of SCLC pathophysiology would create a more comprehensive understanding of this disease with vast therapeutic implications. By appreciating these paradigm-shifting insights, this proposal seeks to uncover the detailed mechanisms by which SCLCs rely upon these powerful neuron-malignant cancer interactions for progression and may uncover innovative angles for therapeutic strategies. Using novel imaging and neuroscience tools uniquely applied in the context of cancer, this proposal aims to further clarify which neurons innervate lung tumors, alter the activity of these neurons to determine the effects on overall SCLC malignant outgrowth, and reciprocally detect changes in these distinct neuronal subpopulations over the course of disease progression to understand the dynamic vulnerabilities of SCLC circuit integration. This proposal makes large conceptual advances, pushing forward our understanding of neuron-cancer interactions by utilizing technological innovation never used in the context of lung cancer. We aim to reframe our perspective of SCLC by investigating how tumor cells in the lung integrate electrical inputs and hijack mechanisms of neural plasticity. A comprehensive understanding of these dynamic malignant-network interactions is necessary to clarify outstanding questions in this emerging field of cancer neuroscience and identify new targets with the potential to change how we treat this devastating disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310475
Entities
People
- Humsa Venkatesh
Organizations
- United States Army