Matrisome analysis of NSCLC unveils clinically-important cancer-associated extracellular matrix changes

Introduction: Non-small cell lung carcinoma (NSCLC), comprising adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), is characterized by an active desmoplastic stroma with an accumulation of extracellular matrix (ECM) proteins. ECM remodeling is a key feature of cancer progression, but the identification of specific therapeutic targets within this compartment remains challenging. Recent studies suggest a link between increased desmoplastic stroma and malignancy in NSCLC, the role of ECM proteins in disease pathogenesis remains unclear. Methods: We analyzed an exploratory cohort of Pan-Cancer Atlas and a study cohort to identify differentially expressed ECM proteins. Our focus was on fibrillar components (elastin, fibrillin, collagens), glycosaminoglycans (chondroitin sulfate and heparan sulfate), and matricellular proteins (SPARC). Bioinformatics analysis highlighted matrix proteins that modulate ECM functionality and structure, potentially serving as biomarkers and/or therapeutic targets. Results: Adenocarcinomas exhibited an ECM enriched with abnormal elastin, chondroitin sulfate, and SPARC. Collagen IV expression in the basement membrane was reduced, while collagen III and V were prominent around tumors. LUSC showed more fibrotic ECM, leading to a stiffer microenvironment. While LUSC's basement membrane may be fragmented, it often retains more intact collagen IV compared to LUAD. High elastin expression in LUAD correlated with smaller tumors (P = 0.022), while fibrillin-2 expression was linked to T1 stage (P = 0.035) and pathological stage I (P = 0.014). In LUSC, elastin expression correlated with negative lymph nodes (P = 0.037). SPARC was an independent factor for overall survival for both subtypes (P < 0.05). Conclusion: This study provides insights into matrix changes in NSCLC and identifies promising candidates for targeted therapies.