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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.
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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