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Open Access Publications from the University of California

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

  • Author(s): Gentles, Andrew J;
  • Hui, Angela Bik-Yu;
  • 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
  • et al.


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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