The tumor microenvironment shows a hierarchy of cell-cell interactions dominated by fibroblasts

Shimrit Mayer, Tomer Milo, Achinoam Isaacson, Coral Halperin, Shoval Miyara, Yaniv Stein, Chen Lior, Meirav Pevsner-Fischer, Eldad Tzahor, Avi Mayo, Uri Alon () and Ruth Scherz-Shouval ()
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Shimrit Mayer: The Weizmann Institute of Science
Tomer Milo: The Weizmann Institute of Science
Achinoam Isaacson: The Weizmann Institute of Science
Coral Halperin: The Weizmann Institute of Science
Shoval Miyara: The Weizmann Institute of Science
Yaniv Stein: The Weizmann Institute of Science
Chen Lior: The Weizmann Institute of Science
Meirav Pevsner-Fischer: The Weizmann Institute of Science
Eldad Tzahor: The Weizmann Institute of Science
Avi Mayo: The Weizmann Institute of Science
Uri Alon: The Weizmann Institute of Science
Ruth Scherz-Shouval: The Weizmann Institute of Science

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract The tumor microenvironment (TME) is comprised of non-malignant cells that interact with each other and with cancer cells, critically impacting cancer biology. The TME is complex, and understanding it requires simplifying approaches. Here we provide an experimental-mathematical approach to decompose the TME into small circuits of interacting cell types. We find, using female breast cancer single-cell-RNA-sequencing data, a hierarchical network of interactions, with cancer-associated fibroblasts (CAFs) at the top secreting factors primarily to tumor-associated macrophages (TAMs). This network is composed of repeating circuit motifs. We isolate the strongest two-cell circuit motif by culturing fibroblasts and macrophages in-vitro, and analyze their dynamics and transcriptomes. This isolated circuit recapitulates the hierarchy of in-vivo interactions, and enables testing the effect of ligand-receptor interactions on cell dynamics and function, as we demonstrate by identifying a mediator of CAF-TAM interactions - RARRES2, and its receptor CMKLR1. Thus, the complexity of the TME may be simplified by identifying small circuits, facilitating the development of strategies to modulate the TME.

Date: 2023
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DOI: 10.1038/s41467-023-41518-w

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