In-depth characterization of a novel aggressive subtype of lung cancer and dissection of exosomal-miRNAs as key-players for early identification

Lung adenocarcinoma (LUAD) is the most common type of non-small-cell lung cancer, and a subset of patients with early-stage LUAD experience relapses and adverse prognosis. Here we identified by a 10-gene prognostic signature an aggressive LUAD subtype, named C1, that is characterized by loss of lung cell lineage and gain of stem cell-like characteristics, along with mutator and immune evasion phenotypes. In addition, with a multi-tiered approach using coupled RNA-seq and miRNA-seq data analysis of a large cohort of lung cancer patients, we found high accuracy in scoring aggressive disease and identified a minimal signature of 7-miRNAs, which we validated in a cohort of FFPE lung adenocarcinoma samples. The results demonstrate the reliability of miRNA-based biomarkers for lung cancer prognostication and make a step forward to the application of miRNA biomarkers in the clinical routine. In line with this, we finally identified a 6-exo-miRNA signature derived from LUAD patients exosomes that is a reliable biomarker to identify the C1-LUAD subtype. Moreover, we also showed that miR-223-3p was significantly enriched in exosomes derived from C1-like cells and acted as a modulator of immune response. Overall, we provide new insights into the molecular and biological features of aggressive C1-LUAD, providing new biomarkers for the early identification of aggressive subtypes of lung cancer.