Discovery of Stromal Regulatory Networks that Suppress Ras-Sensitized Epithelial Cell Proliferation.

Dev Cell 2017 05;41(4):392-407.e6

Solid Tumor Biology Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Molecular Genetics, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210, USA; Department of Cancer Biology and Genetics, McGill University, Montreal, QC H3A 1A1, Canada; Hollings Cancer Center, Medical University of South Carolina, Hollings Cancer Center 124J, 86 Jonathan Lucas Street, Charleston, SC 29425, USA. Electronic address:

Mesodermal cells signal to neighboring epithelial cells to modulate their proliferation in both normal and disease states. We adapted a Caenorhabditis elegans organogenesis model to enable a genome-wide mesodermal-specific RNAi screen and discovered 39 factors in mesodermal cells that suppress the proliferation of adjacent Ras pathway-sensitized epithelial cells. These candidates encode components of protein complexes and signaling pathways that converge on the control of chromatin dynamics, cytoplasmic polyadenylation, and translation. Stromal fibroblast-specific deletion of mouse orthologs of several candidates resulted in the hyper-proliferation of mammary gland epithelium. Furthermore, a 33-gene signature of human orthologs was selectively enriched in the tumor stroma of breast cancer patients, and depletion of these factors from normal human breast fibroblasts increased proliferation of co-cultured breast cancer cells. This cross-species approach identified unanticipated regulatory networks in mesodermal cells with growth-suppressive function, exposing the conserved and selective nature of mesodermal-epithelial communication in development and cancer.

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http://dx.doi.org/10.1016/j.devcel.2017.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508591PMC
May 2017

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