A human lung tumor microenvironment interactome identifies clinically relevant cell-type cross-talk
Andrew J. Gentles, Angela Bik‐Yu Hui, Weiguo Feng, Armon Azizi, Ramesh V. Nair, Gina Bouchard, David A. Knowles, Alice Yu, Youngtae Jeong, Alborz Bejnood, Erna Forgó, Sushama Varma, Yue Xu, Amanda Kuong, Viswam S. Nair, Robert B. West, Matt van de Rijn, Chuong D. Hoang, Maximilian Diehn, Sylvia K. Plevritis
Abstract
BACKGROUND: Tumors comprise a complex microenvironment of interacting malignant and stromal cell types. Much of our understanding of the tumor microenvironment comes from in vitro studies isolating the interactions between malignant cells and a single stromal cell type, often along a single pathway. RESULT: To develop a deeper understanding of the interactions between cells within human lung tumors, we perform RNA-seq profiling of flow-sorted malignant cells, endothelial cells, immune cells, fibroblasts, and bulk cells from freshly resected human primary non-small-cell lung tumors. We map the cell-specific differential expression of prognostically associated secreted factors and cell surface genes, and computationally reconstruct cross-talk between these cell types to generate a novel resource called the Lung Tumor Microenvironment Interactome (LTMI). Using this resource, we identify and validate a prognostically unfavorable influence of Gremlin-1 production by fibroblasts on proliferation of malignant lung adenocarcinoma cells. We also find a prognostically favorable association between infiltration of mast cells and less aggressive tumor cell behavior. CONCLUSION: These results illustrate the utility of the LTMI as a resource for generating hypotheses concerning tumor-microenvironment interactions that may have prognostic and therapeutic relevance.