D108-10 Defining the Role of Cancer Cell Plasticity and Wnt Pathway Activation During Lung Adenocarcinoma Metastasis

Abstract Lung adenocarcinoma (LUAD) is the leading cause of cancer-related mortality worldwide, with prognosis largely determined by disease stage at diagnosis. While early-stage LUAD can be cured by surgery or radiation, outcomes decline sharply once more distant metastasis occurs. The biological mechanisms that enable metastatic progression remain poorly defined. To address this gap, we established a paired patient platform that collects sample from primary lung tumors, lymph node metastases, and pleural effusions from treatment-naïve patients during diagnostic procedures (i.e. bronchoscopy). This approach enables parallel single nucleus RNA sequencing (snRNA-seq) and patient-derived organoid generation from the same specimens, providing an integrated system for transcriptomic and functional analysis of LUAD progression.Preliminary snRNA-seq data reveal that metastatic LUAD cells undergo a marked transcriptional reprogramming. While primary nodules express canonical LUAD markers (TTF-1, NAPSA), a subset of metastatic pleural effusions show loss of these genes and gain of a basal-like signature defined by TP63 and KRT5. These cells also exhibit activation of WNT pathway components (LGR5, LGR6, RSPO3), a pattern reminiscent of fetal lung basal progenitors. Organoid models derived from matched metastatic samples recapitulate this phenotype, and pharmacologic inhibition of WNT signaling suppresses basal marker expression while restoring classical LUAD features. Together, these findings suggest that RSPO-LGR-mediated WNT activity drives acquisition of a plastic, fetal-like basal state that promotes metastasis.Building on these results, we will use expanded paired patient datasets to map LUAD progression at single-cell resolution and to test the requirement and sufficiency of RSPO-LGR-WNT signaling in mediating the TP63+ basal-like transition. Comparative analyses with fetal and adult basal cell atlases will further define the extent to which metastatic LUAD reactivates developmental programs.This work establishes a robust human-derived model for studying LUAD progression within individual patients, linking transcriptomic plasticity to functional behavior. By elucidating how WNT-driven fetal-like reprogramming contributes to metastasis, these studies aim to uncover new therapeutic targets capable of disrupting the cellular plasticity that fuels disease dissemination and treatment resistance in lung adenocarcinoma. This abstract is funded by: Rogel Cancer Center, Michigan Medicine