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

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...

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Detalles Bibliográficos
Autores principales: Mayer, Shimrit, Milo, Tomer, Isaacson, Achinoam, Halperin, Coral, Miyara, Shoval, Stein, Yaniv, Lior, Chen, Pevsner-Fischer, Meirav, Tzahor, Eldad, Mayo, Avi, Alon, Uri, Scherz-Shouval, Ruth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10509226/
https://www.ncbi.nlm.nih.gov/pubmed/37726308
http://dx.doi.org/10.1038/s41467-023-41518-w
Descripción
Sumario: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.