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Published on: October 5, 2020
Discovery of Stromal Regulatory Networks that Suppress Ras-Sensitized Epithelial Cell Proliferation
Huayang Liu1, James A Dowdle1, Safiya Khurshid1
1Solid 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.
Abstract:
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.
Insights
Mesodermal cells regulate epithelial cell growth. Researchers identified 39 genes in these cells that suppress cancer cell proliferation, revealing conserved communication networks in development and disease.
Area of Science:
- Developmental Biology
- Cancer Biology
- Cell Signaling
Background:
- Mesodermal cells influence epithelial cell proliferation in normal and disease contexts.
- Understanding mesodermal-epithelial communication is crucial for development and cancer research.
Purpose of the Study:
- To identify mesodermal factors that suppress epithelial cell proliferation using a genome-wide screen.
- To investigate the conserved role of these factors in mammalian development and breast cancer.
Main Methods:
- Utilized a Caenorhabditis elegans organogenesis model for a mesodermal-specific RNAi screen.
- Performed gene deletion in mouse stromal fibroblasts and analyzed human breast cancer stroma.
- Assessed proliferation of co-cultured human breast cancer cells and fibroblasts.
Main Results:
- Discovered 39 mesodermal factors that suppress proliferation of Ras pathway-sensitized epithelial cells.
- Identified conserved functions in mouse models, where deletion led to mammary gland epithelial hyper-proliferation.
- A 33-gene signature was enriched in human breast cancer stroma; depletion increased cancer cell proliferation.
Conclusions:
- Identified novel mesodermal regulatory networks with conserved growth-suppressive functions.
- Demonstrated the critical role of mesodermal-epithelial communication in controlling epithelial proliferation.
- Highlighted the potential of these findings for understanding and targeting breast cancer development.
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