DDR1 regulates RUNX1-CBFß to control breast stem cell differentiation

The human breast is complex and comprised of multi-lineage and multi-structural elements. Recent work has shown that epithelial stem and progenitor cells use the collagen receptor Discoidin Domain Receptor 1 (DDR1) for differentiation into both basal and luminal cell lineages, which together are necessary for complex ductal-lobular morphogenesis. We developed a next-generation single cell derived organoid model that generates miniaturized breast tissue, to study how single stem cells can give rise to multiple cell types and compound tissue structures. We show that DDR1 activation triggers stem cell differentiation via RUNX1, in turn driving multilineage differentiation as well as complex ductal-lobular development. Mechanistically, DDR1 affects the interaction and expression of RUNX1 and its cofactor CBFß, thereby regulating its activity. Together, these findings contribute to the current understanding of how the extracellular matrix component within the stem cell niche drives organogenesis and tissue regeneration. Overall design: To investigate similarities between gene networks regulated by DDR1 and RUNX1, in an attempt to prove that they may be in the same pathway, MCF10A cells were treated with Collagen or Collagen and either DDR1 or RUNX inhibitors. RNA-seq was performed on these samples, followed by gene expression analysis comparison of differential gene sets from RUNXi and DDR1i treated samples compared to the control.