A human lung tumor microenvironment interactome identifies clinically relevant cell-type cross-talk

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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.

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Gentles, A. J., Hui, A. B. Y., Feng, W., Azizi, A., Nair, R. V., Bouchard, G., … Plevritis, S. K. (2020). A human lung tumor microenvironment interactome identifies clinically relevant cell-type cross-talk. Genome Biology, 21(1). https://doi.org/10.1186/s13059-020-02019-x

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