Mal, Y. | bioRxiv Science

bioRxiv2024

DDR1 regulates RUNX1-CBFβ 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 both ductal and alveolar 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 CBF{beta} 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.

developmental biology↗

bioRxiv2023

Selective inhibition of fibroblast-specific Domain Discoidin Receptor 1 (DDR1) reduces collagen deposition and modulates fibroblast-specific cytokine release within the breast microenvironment.

Fibroblasts are a major cell type within breast microenvironment which play key roles in tissue remodeling during the processes of normal development, injury, and malignancy. During wound healing and tumorigenesis, fibroblasts facilitate production and degradation of the extracellular matrix and produce inflammatory mediators which act as immune regulators. Domain Discoidin Receptor 1 (DDR1) is a cell surface tyrosine kinase receptor expressed by epithelial and stromal cells which is activated by collagen. In the breast, DDR1 expression and activity has been implicated in the development of fibrosis as well as chemotherapy resistance. We set out to examine whether selective inhibition of DDR1 would modulate fibroblast immunomodulatory function to generate an immune-permissive breast microenvironment and reduce stromal desmoplasia. In vivo, DDR1 inhibition resulted in mammary fibroblast tissue remodeling, reduced collagen deposition, and changes in immunomodulatory cytokine expression. Furthermore, DDR1 inhibition was associated with increased CD45.2+ immune cell infiltration and reduced Ly6G+/Ly6C- neutrophil infiltration. Mechanistically, we developed an ex-vivo 3D collagen hydrogel model of desmoplasia to study the effects of DDR1 inhibition on the expression of immune modulating factors and fibroblast functions and features. We found that DDR1 regulates the expression and secretion of key immunomodulatory cytokines (IL-6, IL-8, and MCP-1). Collectively these findings suggest that breast fibroblast-specific DDR1 mediates collagen deposition and immunomodulatory function within the mammary gland and warrants further investigation as a potential target for fibroblast-modulating therapy in benign and neoplastic breast disorders.

cell biology↗