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

Gentles, Andrew J.; Hui, Angela B.; Feng, Weiguo; Azizi, Armon; Nair, Ramesh V.; Bouchard, Gina; Knowles, David A.; Yu, Alice; Jeong, Youngtae; Bejnood, Alborz; Forgó, Erna; Varma, Sushama; Xu, Yue; Kuong, Amanda; Nair, Viswam S.; West, Rob; van de Rijn, Matt; Hoang, Chuong D.; Diehn, Maximilian; Plevritis, Sylvia K.

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.

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.

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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September 22, 2023