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Dev Cell ; 41(4): 392-407.e6, 2017 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-28535374

RESUMEN

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.


Asunto(s)
Células Epiteliales/citología , Células Epiteliales/metabolismo , Redes Reguladoras de Genes , Proteínas ras/metabolismo , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Caenorhabditis elegans/citología , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Linaje de la Célula , Proliferación Celular , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Perfilación de la Expresión Génica , Genoma , Humanos , Glándulas Mamarias Animales/citología , Mesodermo/metabolismo , Ratones , Mutación/genética , Proteínas Nucleares , Especificidad de Órganos , Fenotipo , Proteínas Quinasas , Proteínas Serina-Treonina Quinasas/metabolismo , Interferencia de ARN , Transducción de Señal/genética , Células del Estroma/citología , Células del Estroma/metabolismo , Proteínas Activadoras de ras GTPasa/metabolismo
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