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

Huayang Liu, James A. Dowdle, Safiya Khurshid, Nicholas J. Sullivan, Nicholas Bertos, Komal Rambani, Markus Mair, Piotr Daniel, Esther Wheeler, Xing Tang, Kyle Toth, Michael Lause, Markus E. Harrigan, Karl Eiring, Connor Sullivan, Matthew J. Sullivan, Serena W. Chang, Siddhant Srivastava, Joseph S. Conway, Raleigh Kladney, Joseph McElroy, Sooin Bae, Yuanzhi Lu, Ali Tofigh, Sadiq M.I. Saleh, Soledad A. Fernandez, Jeffrey D. Parvin, Vincenzo Coppola, Erin R. Macrae, Sarmila Majumder, Charles L. Shapiro, Lisa D. Yee, Bhuvaneswari Ramaswamy, Michael Hallett, Michael C. Ostrowski, Morag Park, Helen M. Chamberlin, Gustavo Leone

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.