5. Rachel Davis, BS

Small cell lung cancer (SCLC) is a lethal disease; treatment options are extremely limited and prognosis is poor, with a five-year survival of only 7% (American Cancer Society). An improved understanding of biological drivers of SCLC is necessary to improve treatments and prognosis for these patients. Neurons are now being considered an influential part of the tumor microenvironment in many cancer types, and our lab has previously demonstrated the ability of brain-metastatic SCLC cells to reciprocally communicate directly with cortical neurons to support metastatic progression (Savchuk et. al., 2023, bioRxiv). These findings raised the question of whether progression of primary SCLC within the lung is similarly driven by neuronal activity. In beginning to investigate this question, we found that denervation of the lung by unilateral cervical vagotomy dramatically suppresses the development of SCLC in a genetic mouse model. We are now investigating the mechanisms driving this phenotype, and the current study focuses on first characterizing SCLC tumor innervation patterns within the lung. Using histological and lung-clearing approaches to analyze tumor-burdened lungs from a genetically engineered triple knockout SCLC mouse model, we demonstrate that SCLC tumors i.) preferentially grow in the presence of nerve fibers, ii.) are associated with regions of hyperinnervated airways, and iii.) are intratumorally innervated by nerve fibers of different peripheral nerve populations. We are currently following up these findings with in-vitro and in-vivo functional assays to investigate the contribution of specific nerve populations on SCLC progression, with a focus on direct nerve-cancer interactions.