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Functional delineation of the luminal epithelial microenvironment in breast using cell-based screening in
Tiina A Jokela1, Mark A Dane2, Rebecca L Smith2
1Department of Population Sciences, Center for Cancer and Aging, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Cellular Signalling
|November 7, 2023
Summary
Researchers identified key microenvironment signals regulating mammary luminal epithelial cell growth using a high-throughput microarray. Hepatocyte growth factor (HGF) robustly expanded these cells via MET receptor signaling.
Area of Science:
- Cell Biology
- Developmental Biology
- Tissue Homeostasis
Background:
- Microenvironment signals critically influence cell fate and tissue homeostasis.
- Dissecting the coordinated effects of multiple microenvironment factors on cellular phenotype is experimentally challenging.
Purpose of the Study:
- To identify specific microenvironment factors that support the proliferation and maintenance of primary human mammary luminal epithelial cells.
- To establish a high-dimensional approach for dissecting key microenvironmental signals controlling cellular states.
Main Methods:
- Utilized a high-throughput microenvironment microarray with 2640 unique pairwise signals.
- Employed RNA-sequencing to identify signal-expressing cell types and cognate receptors in vivo.
- Conducted cell-based functional studies to confirm reproducible effects of microenvironment factors.
Main Results:
- Identified multiple factors modulating luminal cell number, including HGF, NRG1, BMP2, and WNT3A.
- Hepatocyte growth factor (HGF) demonstrated the most robust effect, expanding luminal cells via cKit+ progenitors expressing MET receptor.
- Luminal cells from women at high genetic risk for breast cancer showed increased MET receptor expression.
Conclusions:
- The high-dimensional microarray approach effectively dissects critical microenvironmental signals.
- HGF-MET signaling plays a significant role in mammary luminal cell expansion.
- Increased MET receptor in high-risk individuals may contribute to luminal lineage expansion.
