Significance Quantitative mass spectrometric profiling of the extracellular matrix composition of normal lung, fibrotic lung, primary lung tumors, and lung metastases to the lymph nodes uncovered specific signatures distinguishing these tissues. CRISPR/Cas9-mediated gene activation of one of the identified factors, Tenascin-C (Tnc), showed that this protein plays a role in mediating lung adenocarcinoma metastasis. Tnc expression is repressed, directly or indirectly, by the transcription factor Nkx2-1. Bioinformatic analysis shows that expression of three matrisome factors ( TNC , S100A10 , and S100A11 ) can predict survival in patients with lung adenocarcinoma. These factors could serve as disease markers that could be exploited for better diagnosis of lung cancer, and their future study could be used to inform the design of more potent treatments for patients.