Research Projects

Chronic Obstructive Pulmonary Disease (COPD) is a significant risk factor for lung cancer due to chronic inflammation, oxidative stress, and impaired ciliary function, all of which hinder cellular repair. COPD fosters a tumor-promoting microenvironment in the lungs, characterized by persistent inflammation, ciliary dysfunction, and basal cell hyperplasia. Recent studies indicate that dysregulation of cilia-associated genes is frequently observed across cancer types and may contribute to cancer initiation by altering mucociliary clearance and immune surveillance. This research uses a dual-model approach that combines patient-derived lung tissue biopsies and 3D human lung organoids (HLOs) to investigate the molecular mechanisms through which COPD-induced ciliary dysfunction and inflammation drive lung cancer progression. Our overarching hypothesis is that chronic inflammation and ciliary dysfunction in COPD disrupt mucociliary clearance, activating oncogenic pathways such as NF-κB and STAT3, which promote basal cell remodeling, epithelial-mesenchymal transition (EMT), and genetic instability. The project will utilize patient-derived lung biopsies and HLOs to model COPD conditions. HLOs will be exposed to COPD-associated stimuli to mimic chronic inflammation, while patient-derived tissue biopsies will serve as comparative models. Building on my prior work with human nose organoids to study respiratory diseases, this study leverages my expertise in organoid models for investigating complex respiratory mechanisms, providing a robust platform to examine COPD-driven ciliary dysfunction and its role in carcinogenesis. Objectives and Main Experiments: 1: Model COPD-Induced Inflammation and Ciliary Dysfunction: Develop COPD models in HLOs using cigarette smoke or carbon nanoparticles and inflammatory cytokines, validating with patient-derived biopsies. 2: Map Gene Expression and Lung Cancer Pathways: Perform high-resolution spatial mapping of genes linked to COPD-related lung cancer risk, focusing on ciliary function, inflammation, EMT, and key cancer pathways (JAK-STAT, mTOR, Wnt, PI3K-AKT). 3: Investigate Mechanistic Pathways and Identify Biomarkers for Early Diagnosis: Examine how ciliary dysfunction, EMT, and cancer pathways drive lung cancer initiation in COPD. Identify potential biomarkers through single-cell RNA sequencing and test pathway inhibitors to assess impacts on COPD-related cancer progression. Significance: This study addresses a critical gap in understanding the molecular pathways linking COPD to lung cancer. By leveraging advanced single-cell and spatial genomics platforms, we will achieve unprecedented insights into cellular and molecular changes associated with COPD-driven lung carcinogenesis. Findings could enable the development of novel biomarkers for early cancer detection and therapeutic targets focused on ciliary function, inflammation, and EMT, offering substantial benefits for COPD patients at high lung cancer risk.