Simultaneous immunomodulation and epithelial-to-mesenchymal transition drives lung adenocarcinoma progression.
Overview
abstract
Lung cancer remains the deadliest cancer in the United States, with lung adenocarcinoma (LUAD) as its most prevalent subtype. While computed tomography (CT)-based screening has improved early detection and enabled curative surgeries, the molecular and cellular dynamics driving early-stage LUAD progression remain poorly understood, limiting non-surgical treatment options. To address this gap, we profiled 2.24 million cells from 122 early-stage LUAD patients using multiplexed imaging mass cytometry (IMC). This analysis revealed the molecular, spatial, and temporal dynamics of LUAD development. Our findings uncover a binary progression model. LUAD advances through either inflammation, driven by a balance of cytotoxic and regulatory immune activity, or fibrosis, characterized by stromal activation. Surprisingly, tumor cell populations did not increase significantly. Instead, they displayed a mixed phenotypic profile consistent with epithelial-to-mesenchymal transition (EMT), effectively masking the expansion of malignant cells. Furthermore, we addressed discrepancies between CT-based and histology-based subtyping. CT scans, while non-invasive, often mischaracterize invasive fibrotic tumors-which account for 20.5% of LUAD cases-as mild, non-solid ground glass opacities (GGOs). Using high-content IMC imaging, we demonstrate that these tumors harbor significant risks and advocate for improved diagnostic strategies. These strategies should integrate molecular profiling to refine patient stratification and therapeutic decision-making. Altogether, our study provides a high-resolution, systems-level view of the tumor microenvironment in early-stage LUAD. We characterize key transitions in oncogenesis and propose a precision-driven framework to enhance the detection and management of aggressive disease subtypes.
