Growth of lung cancer cells in three-dimensional microenvironments reveals key features of tumor malignancy

Cultured human lung cancer cell lines have been used extensively to dissect signaling pathways underlying cancer malignancy, including proliferation and resistance to chemotherapeutic agents. However, the ability of malignant cells to grow and metastasize in vivo is dependent upon specific cell-cell and cell-extracellular matrix (ECM) interactions, many of which are absent when cells are cultured on conventional tissue culture plastic. Previous studies have found that breast cancer cell lines show differential growth morphologies in three-dimensional (3D) gels of laminin-rich (lr) ECM, and that gene expression patterns associated with organized cell structure in 3D lrECM were associated with breast cancer patient prognosis. We show here that established lung cancer cell lines also can be classified by growth in lrECM into different morphological categories and that transcriptional alterations distinguishing growth on conventional tissue culture plastic from growth in 3D lrECM are reflective of tissue-specific differentiation. We further show that gene expression differences that distinguish lung cell lines that grow as smooth vs. branched structures in 3D lrECM can be used to stratify adenocarcinoma patients into prognostic groups with significantly different outcome, defining phenotypic response to 3D lrECM as a potential surrogate of lung cancer malignancy.